WO2025049814A2 - Compositions de ribonucléotide réductase (rnr) et méthodes d'utilisation - Google Patents

Compositions de ribonucléotide réductase (rnr) et méthodes d'utilisation Download PDF

Info

Publication number
WO2025049814A2
WO2025049814A2 PCT/US2024/044534 US2024044534W WO2025049814A2 WO 2025049814 A2 WO2025049814 A2 WO 2025049814A2 US 2024044534 W US2024044534 W US 2024044534W WO 2025049814 A2 WO2025049814 A2 WO 2025049814A2
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
compound
therapeutic agent
formula
tumor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/044534
Other languages
English (en)
Other versions
WO2025049814A3 (fr
Inventor
Ryan Hansen
Sudhir CHOWDHRY
Shailaja Kasibhatla
Klaus Wolfgang WAGNER
Christian Hassig
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boundless Bio Inc
Original Assignee
Boundless Bio Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boundless Bio Inc filed Critical Boundless Bio Inc
Publication of WO2025049814A2 publication Critical patent/WO2025049814A2/fr
Publication of WO2025049814A3 publication Critical patent/WO2025049814A3/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides by removing the 2’-hydroxyl group of the ribose ring of nucleotide diphosphates. These deoxyribonucleotides are used in the synthesis of DNA.
  • a selective ribonucleotide reductase (RNR) inhibitor and the therapeutic agent comprising administering a selective ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject, wherein the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor and/or a receptor tyrosine kinase (RTK) inhibitor, and wherein the method results in a delay or prevention of resistance by a tumor or tumor cells to the therapeutic agent.
  • the method results in the inhibition of growth of the tumor or proliferation of the tumor cells.
  • the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors.
  • the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR/MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.
  • the therapeutic agent comprises a BRAF inhibitor and a second inhibitor.
  • the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor.
  • the therapeutic agent comprises a KRAS inhibitor and a second inhibitor.
  • the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor, or an S0S1 inhibitor.
  • the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.
  • the therapeutic agent and the RNR inhibitor are administered concurrently.
  • the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.
  • the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene. In some embodiments, the focal amplification is less than 20 Mb. In some embodiments, the tumor or tumor cells comprise an ecDNA signature. In some embodiments, the tumor or tumor cells are ecDNA competent. In some embodiments, the focal amplification is comprised on ecDNA. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRAS G12C , KRAS G12V or a KRAS G12D mutation.
  • the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC- 376, garsorasib, GEC-255, GF-105, GH-35, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.
  • KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001
  • the therapeutic agent comprises a BRAF inhibitor
  • the tumor or tumor cells comprise a BRAFV600E mutation.
  • the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.
  • the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.
  • a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafen
  • the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS 1553. In some embodiments, the method further comprises administering an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH- 7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD- 9008, E01001, E-10C, epertin
  • the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene.
  • the mutation is BRAF V600E , KRAS G12C , KRAS G12V or KRAS G12D .
  • the mutation is selected from a KRAS mutation described in Table 1.
  • the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof.
  • NGS next generation sequencing
  • the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.
  • RNR selective ribonucleotide reductase
  • the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor and/or a receptor tyrosine kinase (RTK) inhibitor.
  • the method results in the inhibition of growth of the tumor or proliferation of the tumor cells.
  • the therapeutic agent comprises one or more inhibitors.
  • the therapeutic agent comprises at least two inhibitors.
  • the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR/MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.
  • the therapeutic agent comprises a BRAF inhibitor and a second inhibitor.
  • the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor.
  • the therapeutic agent comprises a KRAS inhibitor and a second inhibitor.
  • the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor, or an S0S1 inhibitor.
  • inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone.
  • the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.
  • the therapeutic agent and the RNR inhibitor are administered concurrently. The method of any one of claims 1 to 13, wherein the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.
  • the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene.
  • the focal amplification is less than 20 Mb.
  • the tumor or tumor cells comprise an ecDNA signature.
  • the tumor or tumor cells are ecDNA competent.
  • the focal amplification is comprised on ecDNA.
  • the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRAS G12C , a KRAS G12V , or a KRAS G12D mutation.
  • the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, HBI-2438, HRS- 4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL- 15293, ZG-19018, and any combination thereof.
  • KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001
  • the therapeutic agent comprises a BRAF inhibitor
  • the tumor or tumor cells comprise a BRAFV600E mutation.
  • the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.
  • the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL- 102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.
  • a BRAF inhibitor selected from the group consisting of ABM-1310, APL- 102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifira
  • the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS1553. In some embodiments, the method further comprises administering an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL- 1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS- 2087, DZD-9008, E01001, E-10C, epertin
  • the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene.
  • the mutation is BRAF V600E , KRAS G12C , KRAS G12V , or KRAS G12D .
  • the mutation is selected from a KRAS mutation described in Table 1.
  • the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof.
  • NGS next generation sequencing
  • the amplification of the RTK or MAPK gene is detected by NGS.
  • the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.
  • a therapeutic agent comprising administering a selective ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject, wherein the therapeutic agent is a mitogen -activated protein kinase (MAPK) pathway inhibitor and/or a receptor tyrosine kinase (RTK) inhibitor, wherein the subject has been previously treated with the therapeutic agent and demonstrated decreased responsiveness or resistance to the therapeutic agent, and wherein the method results in inhibition of growth of the tumor or proliferation of the tumor cells.
  • RNR selective ribonucleotide reductase
  • the therapeutic agent is a mitogen -activated protein kinase (MAPK) pathway inhibitor and/or a receptor tyrosine kinase (RTK) inhibitor
  • the subject has been previously treated with the therapeutic agent and demonstrated decreased responsiveness or resistance to the therapeutic agent
  • the method results in inhibition of growth of the tumor or proliferation of the tumor cells.
  • the therapeutic agent comprises one or more inhibitors.
  • the therapeutic agent comprises
  • the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR/MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.
  • the therapeutic agent comprises a BRAF inhibitor and a second inhibitor.
  • the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor.
  • the therapeutic agent comprises a KRAS inhibitor and a second inhibitor.
  • the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor, or an SOS 1 inhibitor.
  • inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone.
  • the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.
  • the therapeutic agent and the RNR inhibitor are administered concurrently.
  • the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.
  • the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene.
  • the focal amplification is less than 20 Mb.
  • the tumor or tumor cells comprise an ecDNA signature.
  • the tumor or tumor cells are ecDNA competent.
  • the focal amplification is comprised on ecDNA.
  • the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRAS G12C , a KRAS G12V , or a KRAS G12D mutation.
  • the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS- 4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY- 3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.
  • KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001
  • the therapeutic agent comprises a BRAF inhibitor
  • the tumor or tumor cells comprise a BRAFV600E mutation.
  • the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.
  • the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.
  • a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, li
  • the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS 1553. In some embodiments, the method further comprises administering an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD- 9008, E01001, E-10C, epertini
  • the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene.
  • the mutation is BRAF V600E , KRAS G12C , KRAS G12V , or KRAS G12D .
  • the mutation is selected from a KRAS mutation described in Table 1.
  • the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof.
  • NGS next generation sequencing
  • the amplification of the RTK or MAPK gene is detected by NGS.
  • the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.
  • a tumor or tumor cells in a subject that are resistant to a therapeutic agent comprising administering a selective ribonucleotide reductase (RNR) inhibitor to the subject, wherein the tumor or tumor cells comprise a focal amplification of a mitogen activated protein kinase (MAPK) pathway gene or a receptor tyrosine kinase (RTK) gene, wherein the therapeutic agent targets the MAPK pathway gene or the RTK gene, and where the method results in inhibition of growth of the tumor or proliferation of the tumor cells.
  • RNR selective ribonucleotide reductase
  • the therapeutic agent targets KRAS.
  • the therapeutic agent targets KRAS G12C , KRAS G12V , or KRAS G12D .
  • the therapeutic agent targets a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the focal amplification is comprised on ecDNA.
  • the therapeutic agent is a KRAS inhibitor.
  • the KRAS inhibitor is selected from the group consisting of adagrasib, AIG Oncol, BBO- 8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, glecirosib, HBI-2438, HRS-4642, HS- 10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.
  • the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. In some embodiments, the RNR inhibitor is TAS 1553. In some embodiments, the copy number of one or more oncogenes associated with the focal amplification is reduced after administering the selective RNR inhibitor.
  • a method of treating a tumor or tumor cells comprising administering a selective ribonucleotide reductase (RNR) inhibitor, wherein the tumor cells comprise ecDNA-derived amplification of an oncogene, and wherein the treatment reduced the level of amplification of the oncogene.
  • RNR selective ribonucleotide reductase
  • the size of the tumor or growth of the tumor or growth of the tumor cells is inhibited after treatment with the selective RNR inhibitor.
  • the focal amplification is comprised on ecDNA.
  • the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the RNR inhibitor is TAS1553.
  • FIG. 1 shows mean tumor growth of CT26WT E3 G12C KRAS mutant tumor cells implanted in mice treated with vehicle compared with mice treated with adagrasib.
  • FIG. 2 shows Kras positive ecDNA manually quantified in ex vivo metaphase arrested tumors cells isolated from CT26WT E3 G12C KRAS tumors grown in mice that are untreated or treated with vehicle compared with mice treated with adagrasib.
  • FIG. 3 shows mean tumor growth of CT26WT E3 G12C KRAS mutant tumor cells implanted in mice after starting treatment with vehicle, adagrasib, Compound 1, or Compound 1 with adagrasib.
  • FIG. 4 shows mean tumor growth of CT26WT E3 G12C KRAS mutant adagrasib resistant ecDNA+ tumor cells implanted in mice after starting treatment with vehicle, adagrasib, Compound 1, or Compound 1 with adagrasib.
  • FIG. 5 shows mean tumor growth of WiDr V600E BRAF mutant tumor cells implanted in mice after starting treatment with vehicle, cetuximab and encorafenib, Compound 1, or Compound 1 with cetuximab and encorafenib.
  • FIG. 6A shows percent of tumors that are less than 500 mm 3 for tumors established in mice implanted with WiDr V600E BRAF mutant tumor cells during the course of treatment with vehicle, cetuximab and encorafenib, Compound 1, or Compound 1 with cetuximab and encorafenib.
  • FIG. 6B shows mean body weight change from starting mean body weight in mice treated with vehicle, cetuximab and encorafenib, Compound 1, or Compound 1 with cetuximab and encorafenib.
  • FIG. 7 shows mean tumor growth of SNU-16 FGFR2 ecDNA+ tumor cells implanted in mice after treatment with vehicle only; infigratinib, Compound 1 or Compound 1 and infigratinib.
  • FIGS. 8A-E show the impact on ecDNA levels upon inhibition of RNR by Compound 1 treatment using multiple orthogonal readouts.
  • FIG. 8A shows cell-death and viability assessment using Trypan Blue staining.
  • FIG. 8B shows FISH based cytogenetic analysis of cells treated with Compound 1.
  • FIG. 8C and 8D show quantification of the FISH signals, using the image quantification platform called ImageJ (Tool, Find maxima).
  • FIG. 8E shows the reduction in ecDNA cargo oncoprotein expression of MYC and FGFR2 and replication stress (RS), DNA damage and cell death protein biomarkers using western blotting.
  • RS replication stress
  • FIGS. 9 A-C show that Compound 1 prevents ecDNA -mediated resistance associated with KRASG12C inhibitor in a colorectal cancer model of CT26 cells engineered to express the Kras G12C allele (CT26WT E3), using this cell line in its non-amplified state and after the cells developed resistance to adagrasib.
  • FIG. 9A shows ecDNA and Kras amplification via FISH for CT26 KRASG12C mutant nonamplified cells and adagrasib resistant tumor cells with KRASG12C amplified on ecDNA.
  • FIG. 9B shows a cell proliferation assay confirming resistance generation against adagrasib.
  • FIG. 10A shows the antitumor efficacy of Compound 1 (triangle) and adagrasib (square) monotherapy and Compound 1 plus adagrasib combination therapy (diamond) in the CT26WT E3 tumor model as measured by tumor volume. Data shown as mean ⁇ SEM (standard error of the mean) for each treatment arm.
  • the combination therapy of Compound 1 at 50mg/kg SC BID Q2D plus adagrasib also showed significantly greater antitumor activity when compared with adagrasib monotherapy (**P ⁇ 0.01) on Study Day 30.
  • FIG. 10B shows percent of tumors that are less than 500 mm 3 for tumors established in mice implanted with CT26WT E3 cells during the course of treatment of Compound 1 and adagrasib monotherapy as compared to Compound 1 plus adagrasib combination therapy.
  • FIG. 10C shows the Kras gene copy number determined in terminal tumors and shows that adagrasib results in Kras amplification in resistant tumors and Compound 1 abrogates this amplification.
  • FIG. HA shows the schema for the dosing of the KRAS inhibitor MRTX1133 and Compound 1 over the 8 weeks in Ct26 / ' t ''’ (,l 2l) colorectal cells.
  • FIG. 11B shows a FISH image of a parental (untreated) CT26 /; '' t ''" (,l 2l) CRC colorectal cells and the appearance of ecDNA in the cells treated with increasing doses of MRTX1133 which developed acquired resistance to KRASG12Di by driving KRAS amplifications on ecDNA.
  • FIG. 11C shows cell viability of CT26 Xra? ' G12D CRC colorectal cells parental line, cells that developed resistance to MRTX1133 and cells treated with a combination treatment of
  • MRTX1 133 + Compound 1 showing that the combination led to a significant antiproliferation activity when compared to MRTX1133 alone treated cells (left graph).
  • the bar graph (right graph) shows the copy number (CNV) of KRAS at week 8 for the cells treated in the graph on the left.
  • the combination treatment shows suppression of resistance mediated KRAS amplifications is concomitant with the reduction of cell viability shown in graph on left.
  • RNR Ribonucleotide reductase plays a fundamental role in supporting extrachromosomal DNA (ecDNA) assembly and repair. As such, cellular reliance on RNR is elevated in ecDNA containing cells.
  • RNR is the rate-limiting enzyme responsible for cellular production of deoxyribonucleotide triphosphate (dNTP), the building blocks for DNA, including assembly and repair of ecDNA. It has been found that therapeutic inhibition of RNR dysregulates dNTP production and creates synthetic lethality in ecDNA+ tumor cells.
  • RNR is clinically validated via gemcitabine (gem) and hydroxyurea (HU).
  • non- selective RNR inhibitors such as gem and HU have suboptimal potency (HU) or lack of oral bioavailability (gem), which limits their efficacy and safety in treating ecDNA+ cancers.
  • selective RNR inhibition results in depletion of dNTPs and reduced ecDNA levels in ecDNA-enabled tumor cells, which leads to tumor cell death.
  • kits for treating cancer in a subject comprising administration of a selective ribonucleotide reductase (RNR) inhibitor.
  • RNR selective ribonucleotide reductase
  • the cancer is resistant to a therapeutic agent.
  • the method comprises administering a therapeutic agent with the RNR inhibitor.
  • the method treats resistance to the therapeutic agent.
  • the method prevents or delays resistance to the therapeutic agent.
  • the method comprises administering a selective RNR inhibitor and the therapeutic agent to the subject.
  • the therapeutic agent is a mitogen- activated protein kinase (MAPK) pathway inhibitor.
  • the therapeutic agent is a receptor tyrosine kinase (RTK) inhibitor.
  • the method results in a delay or prevention of resistance by a tumor or tumor cells to the therapeutic agent.
  • the method results in the inhibition of growth of the tumor or proliferation of the tumor cells.
  • the therapeutic agent comprises a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR/MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.
  • the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor or an S0S1 inhibitor.
  • inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone.
  • the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.
  • the therapeutic agent and the RNR inhibitor are administered concurrently. In some embodiments, the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.
  • the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene.
  • the focal amplification is less than 20 Mb.
  • the focal amplification is comprised on ecDNA.
  • the tumor or tumor cells comprise an ecDNA signature.
  • the tumor or tumor cells are ecDNA competent.
  • the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRAS G12C , a KRAS G12V or a KRAS G12D mutation.
  • the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH- 35, glecirosib, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC- 6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.
  • KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX
  • the therapeutic agent comprises a BRAF inhibitor
  • the tumor or tumor cells comprise a BRAF V600E mutation.
  • the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.
  • the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.
  • a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, li
  • the RNR inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the RNR inhibitor comprises a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the method further comprises administering an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH- 7233163, CK-101, CMAB-017, DFP-17729, dacomitini
  • the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene.
  • the mutation is BRAF V600E , KRAS G12C , KRAS G12V or KRAS G12D .
  • the mutation is selected from a KRAS mutation described in Table 1.
  • the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof.
  • NGS next generation sequencing
  • the amplification of the RTK or MAPK gene is detected by NGS.
  • the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.
  • the method comprises administering a selective ribonucleotide reductase (RNR) inhibitor and a therapeutic agent to the subject.
  • RNR selective ribonucleotide reductase
  • the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor.
  • the therapeutic agent is a receptor tyrosine kinase (RTK) inhibitor.
  • the method results in inhibition of growth of the tumor or proliferation of the tumor cells.
  • the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR/MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.
  • the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor or an S0S1 inhibitor.
  • inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone.
  • the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.
  • the therapeutic agent and the RNR inhibitor are administered concurrently. In some embodiments, the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.
  • the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene.
  • the focal amplification is less than 20 Mb.
  • the focal amplification is comprised on ecDNA.
  • the tumor or tumor cells comprise an ecDNA signature.
  • the tumor or tumor cells are ecDNA competent.
  • the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRAS G12C , a KRAS G12V or a KRAS G12D mutation.
  • the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-I8239II, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-I05, GH-35, glecirosib, HBI-2438, HRS- 4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-629I, RMC-9805, sotorasib, YL- 15293, ZG-19018, and any combination thereof.
  • KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-I8239II, BPI
  • the therapeutic agent comprises a BRAF inhibitor
  • the tumor or tumor cells comprise a BRAF V600E mutation.
  • the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.
  • the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL- 102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.
  • a BRAF inhibitor selected from the group consisting of ABM-1310, APL- 102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafinib, encorafenib, exarafenib, lifira
  • the RNR inhibitor comprises a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the RNR inhibitor comprises a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the method further comprises administering an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, BLU-945, BPI-7711, BPI- 361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB-017, DFP-17729, dacomitinib, depatuxizumab, dositinib, DS-2087, DZD-9008, E01001, E-10C, epertinib
  • the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene.
  • the mutation is BRAF V600E , KRAS G12C , KRAS G12V or KRAS G12D .
  • the mutation is selected from a KRAS mutation described in Table 1.
  • the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof.
  • NGS next generation sequencing
  • the cells comprise a focal amplification of one or more oncogenes and the copy number of one or more the oncogenes is reduced after administering the selective RNR inhibitor.
  • the method comprises administering a ribonucleotide reductase (RNR) inhibitor and the therapeutic agent to the subject.
  • RNR ribonucleotide reductase
  • the therapeutic agent is a mitogen-activated protein kinase (MAPK) pathway inhibitor.
  • the therapeutic agent is a receptor tyrosine kinase (RTK) inhibitor.
  • the subject has been previously treated with the therapeutic agent.
  • after treatment the subject demonstrated decreased responsiveness to the therapeutic agent.
  • after treatment the subject demonstrated resistance to the therapeutic agent after treatment the subject demonstrated.
  • the method results in inhibition of growth of the tumor or proliferation of the tumor cells.
  • the therapeutic agent comprises an inhibitor selected from the group consisting of a BRAF inhibitor, CRAF inhibitor, an EGFR inhibitor, an FGFR inhibitor, a MET inhibitor, a dual EGFR/MET inhibitor, a KRAS inhibitor, a pan-RAS inhibitor, a MEK inhibitor, an ERK inhibitor, a SHP2 inhibitor, and a S0S1 inhibitor.
  • the therapeutic agent comprises one or more inhibitors. In some embodiments, the therapeutic agent comprises at least two inhibitors. In some embodiments, the therapeutic agent comprises a BRAF inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises a MEK inhibitor or an EGFR inhibitor. In some embodiments, the therapeutic agent comprises a KRAS inhibitor and a second inhibitor. In some embodiments, the second inhibitor comprises an EGFR inhibitor, a SHP2 inhibitor or an S0S1 inhibitor.
  • inhibition of the growth of the tumor or the proliferation of the tumor cells is greater than inhibition resulting from administering the therapeutic agent alone or the RNR inhibitor alone.
  • the effect of administration of the RNR inhibitor and the therapeutic agent is synergistic.
  • the therapeutic agent and the RNR inhibitor are administered concurrently. In some embodiments, the therapeutic agent and the RNR inhibitor are administered sequentially. In some embodiments, the method further comprises a washout period of no administration of the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the subject failed treatment with the therapeutic agent prior to administration of the RNR inhibitor and the therapeutic agent.
  • the failed treatment comprises progression of disease, continued growth of the tumor, or continued proliferation of the tumor cells.
  • the tumor or tumor cells comprise a focal amplification of a MAPK pathway gene or a receptor tyrosine kinase (RTK) gene.
  • the focal amplification is less than 20 Mb.
  • the focal amplification is comprised on ecDNA.
  • the tumor or tumor cells comprise an ecDNA signature.
  • the tumor or tumor cells are ecDNA competent.
  • the therapeutic agent comprises a KRAS inhibitor and the tumor or tumor cells comprise a KRAS G12C , a KRAS G12V or a KRAS G12D mutation.
  • the tumor or tumor cells comprise a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the subject has a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • a cancer selected from the group consisting of appendix cancer, biliary tract cancer, breast cancer, colorectal cancer, esophageal cancer, gastroesophageal junction cancer, glioblastoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, small bowel cancer, and uterine cancer.
  • the therapeutic agent comprises a KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC-376, garsorasib, GEC-255, GF-105, GH-35, glecirosib, HBI- 2438, HRS-4642, HS-10370, JDQ-443, LY-3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.
  • KRAS inhibitor selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX
  • the therapeutic agent comprises a BRAF inhibitor
  • the tumor or tumor cells comprise a BRAF V600E mutation.
  • the subject has a cancer selected from the group consisting of bladder cancer, brain glioblastoma multiforme, brain lower grade glioma, chronic lymphocytic leukemia, colon adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, head and neck thyroid carcinoma, kidney renal papillary cell carcinoma, liver cancer, lung adenocarcinoma, malignant lymphoma, melanoma, metastatic melanoma, ovarian cancer, papillary thyroid cancer, pediatric brain cancer, rectum adenocarcinoma, skin adenocarcinoma, skin cutaneous melanoma, thyroid cancer, and urothelial cancer.
  • the therapeutic agent comprises a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, lifirafenib, LUT-104, naporafenib, pazopanib, PF-07799933, plixorafenib, QLH11906, regorafenib, RX-208, tovorafenib, vemurafenib, WTX-212, and any combination thereof.
  • a BRAF inhibitor selected from the group consisting of ABM-1310, APL-102, BDTX-4933, belvarafenib, brimarafenib, CFT-1946, dabrafmib, encorafenib, exarafenib, li
  • the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the method further comprises administering an EGFR inhibitor.
  • the EGFR inhibitor is selected from the group consisting of 705, 707, 7602, abivertinib, ABX-900, afatinib, alflutinib mesylate, agerafenib (RXDX-105), amivantamab, APL-1898, ASK-120067, aumolertinib (almonertinib), BBT-176, BDTX-189, BDTX-1535, BEBT-109, befortinib mesylate, beitatini, BLU-701, B LU-945, BPI-7711, BPI-361175, BPI-D0316, C-005, CDP1, cetuximab, CH-7233163, CK-101, CMAB- 017, DFP- 17729, dacomitinib
  • the tumor or tumor cells are identified as having a mutation of a MAPK pathway gene and an amplification of a RTK or a MAPK gene.
  • the mutation is BRAF V600E , or KRAS G12C , KRAS G12V or KRAS G12D .
  • the mutation is selected from a KRAS mutation described in Table 1.
  • the amplification of the RTK or MAPK pathway gene is detected by next generation sequencing (NGS), tissue biopsy, liquid biopsy, or a combination thereof.
  • NGS next generation sequencing
  • the method comprises administering a selective ribonucleotide reductase (RNR) inhibitor to the subject, wherein the tumor or tumor cells comprise a focal amplification of a mitogen activated protein kinase (MAPK) pathway gene or a receptor tyrosine kinase (RTK) gene, wherein the therapeutic agent targets the MAPK pathway gene or the RTK gene, and where the method results in inhibition of growth of the tumor or proliferation of the tumor cells.
  • RNR selective ribonucleotide reductase
  • the therapeutic agent targets KRAS.
  • the therapeutic agent targets KRAS G12C , KRAS G12V or KRAS G12D .
  • the therapeutic agent targets a KRAS mutation selected from a KRAS mutation described in Table 1.
  • the focal amplification is comprised on ecDNA.
  • the therapeutic agent is a KRAS inhibitor.
  • the KRAS inhibitor is selected from the group consisting of adagrasib, AIG Oncol, BBO-8520, BBP-454, BEBT-607, BI-1823911, BPI-421286, BTX2541, D3S-001, divarasib, ERAS-3490, ERAS-4057, FMC- 376, garsorasib, GEC-255, GF-105, GH-35, glecirosib, HBI-2438, HRS-4642, HS-10370, JDQ-443, LY- 3537982, MK-1084, MRTX-1133, RMC-6291, RMC-9805, sotorasib, YL-15293, ZG-19018, and any combination thereof.
  • the RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.
  • the copy number of one or more oncogenes associated with the focal amplification is reduced after administering the selective RNR inhibitor.
  • selective RNR inhibitors provided herein have an optimized profile including potency; selectivity for RNR; oral bioavailability; favorable absorption, distribution, metabolism, and excretion (ADME); and clean safety pharmacology.
  • the selective RNR inhibitor is TAS 1553.
  • the selective RNR inhibitor is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • Ring C is a 4- to 8-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N; each R 5 is independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl; or 2 R 5 on the same carbon are taken together to form an oxo; p is 0-4;
  • the compound is of Formula: .
  • the selective RNR inhibitor is a compound of Formula (I-1), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof: Formula (1-1).
  • the compound is of Formula:
  • the selective RNR inhibitor is a compound of Formula (1-2), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
  • the compound is of Formula:
  • the selective RNR inhibitor is a compound of Formula (1-3), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
  • the compound is of Formula:
  • the selective RNR inhibitor is a compound of Formula (1-4), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
  • the compound is of Formula:
  • Ring A is a 5 -membered ring comprising 1 or 2 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5 -membered ring comprising 2 or 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered ring comprising 2-4 heteroatoms selected from the group consisting of O, S, and N.
  • Ring A is a 5-membered ring comprising 1-3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 3 or 4 heteroatoms selected from the group consisting of O, S, and N.
  • Ring A is a 5-membered ring comprising 1 heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered ring comprising 2 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I- 4), Ring A is a 5 -membered ring comprising 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 4 heteroatoms selected from the group consisting of O, S, and N.
  • Ring A is a 5 -membered ring comprising 1 or 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 2 or 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered ring comprising 2-4 heteroatoms selected from the group consisting of O and N.
  • Ring A is a 5-membered ring comprising 1-3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 3 or 4 heteroatoms selected from the group consisting of O and N.
  • Ring A is a 5-membered ring comprising 1 heteroatom selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 2 heteroatoms selected from the group consisting of O and N.
  • Ring A is a 5-membered ring comprising 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered ring comprising 4 heteroatoms selected from the group consisting of O and N.
  • Ring A is a 5 -membered heterocycloalkyl or a 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a 5 -membered heterocycloalkyl comprising one to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring A is a 5 -membered heterocycloalkyl comprising two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5 -membered heterocycloalkyl comprising three to four heteroatoms selected from the group consisting of
  • Ring A is a 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered heteroaryl comprising one to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 5-membered heteroaryl comprising two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (I- l)-(I-4), Ring A is a 5-membered heteroaryl comprising three to four heteroatoms selected from the group consisting of O, S, and N.
  • Ring A is a triazole or tetrazole. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a triazole. In some embodiments of a compound of Formula (I) or (I- 1 )-(I-4), Ring A is a tetrazole. In some embodiments of a compound of Formula (I) or (I-l)-(I-4), Ring A is a 2,3-dihydro-l,3,4-oxadiazole.
  • each R 6 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; or two R 6 on the same atom are taken together to form an oxo.
  • each R 6 is independently deuterium, halogen, or C1-C6alkyl; or two R 6 on the same atom are taken together to form an oxo.
  • each R 6 is independently C1-C6alkyl; or two R 6 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), each R 6 is independently C1-C6alkyl. [00102] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), two R 6 on the same atom are taken together to form an oxo. [00103] In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 0-2.
  • n is 0 or 1. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 1 or 2. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 2 or 3. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 0. In some embodiments of a compound of Formula (I) or (I-1)-(I-4), n is 1. In some embodiments of a compound of Formula (I) or (I- 1)-(I-4), n is 2.
  • n is 3.
  • the compound is of Formula (Ia): wherein R 6’ is hydrogen or C1-C6alkyl.
  • R 6’ is hydrogen or C1-C6alkyl.
  • the compound is of Formula: .
  • X 1 is N.
  • X 1 is CR 1 .
  • X 2 is N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X 2 is CR 2 . [00108] In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X 3 is N. In some embodiments of a compound of Formula (I), (Ia), or (I-1)-(I-4), X 3 is CR 3 . [00109] In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), X 4 is N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), X 4 is CR 4 .
  • Ring C is a 5- to 7- membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
  • Ring C is a 6- to 7-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
  • Ring C is a 5- to 6-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
  • Ring C is a 5-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
  • Ring C is a 6-membered heterocycloalkyl optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N.
  • Ring C is a 5- to 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.
  • Ring C is a 6- to 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.
  • Ring C is a 5- to 6- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 5- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 6- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.
  • Ring C is a 7- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 8- membered heterocycloalkyl comprising 1 additional heteroatom selected from the group consisting of O, S, and N.
  • Ring C is a 5- to 7- membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 6- to 7-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I- l)-(I-4), Ring C is a 5-membered heterocycloalkyl.
  • Ring C is a 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (I-l)-(I-4), Ring C is a 7-membered heterocycloalkyl.
  • the compound is of Formula (lb): wherein R 6’ is hydrogen or C1-C6alkyl; and each R 5’ is independently hydrogen or R 5 .
  • the compound is of Formula: .
  • each R 5’ is independently hydrogen, deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl; or 2 R 5 on the same carbon are taken together to form an oxo.
  • each R 5’ is independently hydrogen, deuterium, halogen, or C1-C6alkyl.
  • each R 5’ is independently hydrogen or C1-C6alkyl.
  • each R 5’ is hydrogen.
  • each R 5’ is independently hydrogen or deuterium.
  • the compound is of Formula (Ic): Formula (Ic); wherein R 6’ is hydrogen or C 1 -C 6 alkyl.
  • the compound is of Formula: .
  • the compound is of Formula (Id): Formula (Id); wherein R 6’ is hydrogen or C1-C6alkyl.
  • the compound is of Formula: .
  • R 6’ is hydrogen.
  • each R 5 is independently deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl; or 2 R 5 on the same carbon are taken together to form an oxo.
  • each R 5 is independently deuterium, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R 5 is independently deuterium. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), each R 5 is independently C1-C6alkyl. [00122] In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 0 or 1.
  • p is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 0. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)- (I-4), p is 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), p is 3.
  • R 1 , R 2 , R 3 , and R 4 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.
  • R 1 , R 2 , R 3 , and R 4 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.
  • R 1 , R 2 , R 3 , and R 4 are independently hydrogen, or halogen, -OR a .
  • R 1 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is halogen.
  • R 2 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is hydrogen, halogen, -OH, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is halogen.
  • R 3 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl.
  • R 3 is hydrogen, halogen, -OH, -OR a , C1-C6alkyl, or C1-C6haloalkyl.
  • R 3 is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is halogen.
  • R 4 is hydrogen, deuterium, halogen, - CN, -OH, -OR a , -NR c R d , C1-C6alkyl, or C1-C6haloalkyl.
  • R 4 is hydrogen, halogen, -OH, -OR a , C1-C6alkyl, or C1-C6haloalkyl.
  • R 4 is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen or halogen. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen, halogen, or -OR a . In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is halogen.
  • R 7 is deuterium, halogen, -CN, -NO 2 , -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R 7 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C 1 -C 6 alkyl or cycloalkyl. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C 1 -C 6 alkyl.
  • Ring B is 6-membered heteroaryl.
  • each R 9 is independently halogen or C1-C6alkyl.
  • m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0 or 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0-2.
  • m is 1-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1 or 2. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 0-3. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 1. In some embodiments of a compound of Formula (I), (Ia)-(Id), or (I-1)-(I-4), m is 2.
  • the selective RNR inhibitor is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof the compound is of Formula: .
  • Ring C is a 5- to 8-membered heterocycloalkyl comprising one or two additional heteroatoms selected from the group consisting of -O-, -S-, and -NR 10 -.
  • Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and - NR 10 -. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 5- to 8-membered heterocycloalkyl comprising one additional heteroatom that is -NR 10 -.
  • Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR 10 -.
  • Ring C is a 5- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and - NR 10 -.
  • Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR 10 -.
  • Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and - NR 10 -. -. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 6- to 7-membered heterocycloalkyl comprising one additional heteroatom that is -NR 10 -.
  • Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR 10 -.
  • Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and -NR 10 -.
  • Ring C is a 6-membered heterocycloalkyl comprising one additional heteroatom that is -S-.
  • Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O-, -S-, and -NR 10 -.
  • Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom selected from the group consisting of -O- and -NR 10 -. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is - NR 10 -. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is -O-. In some embodiments of a compound of Formula (II), Ring C is a 7-membered heterocycloalkyl comprising one additional heteroatom that is -S-.
  • each R 5 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R 5 is independently deuterium, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II), each R 5 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), each R 5 is independently C 1 -C 6 alkyl. [00145] In some embodiments of a compound of Formula (II), two R 5 on the same carbon are taken together to form an oxo.
  • two R 5 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R.
  • two R 5 on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • one R 5 and R 10 are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R.
  • p is 0-3. In some embodiments of a compound of Formula (II), p is 0-2. In some embodiments of a compound of Formula (II), p is 0 or 1. In some embodiments of a compound of Formula (II), p is 1 or 2. In some embodiments of a compound of Formula (II), p is 1-3. In some embodiments of a compound of Formula (II), p is 1. In some embodiments of a compound of Formula (II), p is 2. In some embodiments of a compound of Formula (II), p is 3. [00150] In some embodiments, the compound of Formula (II) is of Formula (Ila): wherein:
  • R 2 is hydrogen, deuterium, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 2 is halogen. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 2 is chloro. [00173] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X 3 is CR 3 .
  • X 3 is N.
  • R 3 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , - C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.
  • R 3 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R 3 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 3 is hydrogen. [00175] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X 4 is CR 4 . In some embodiments of a compound of Formula (II) or (IIa)-(IIc), X 4 is N.
  • R 7 is C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 7 is C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 7 is C1-C6alkyl.
  • R 7 is halogen, -CN, -NO2, -OH, -OR a , C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
  • R 7 is C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl.
  • R 8 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 8 is hydrogen.
  • Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is phenyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is pyridinyl.
  • each R 9 is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 9 is independently halogen or C 1 -C 6 alkyl. [00181] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 0-2.
  • m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1-3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 2 or 3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 0. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 2.
  • each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl.
  • each R a is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1-C6alkyl.
  • each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, cycloalkyl, or heterocycloalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R a is hydrogen.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, or heterocycloalkyl.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl.
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are independently C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R c and R d are hydrogen.
  • the selective RNR inhibitor is a compound, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is selected from a compound of Table 2: TABLE 2 [00187]
  • the absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.
  • the selective RNR inhibitor is a compound, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is selected from a compound of Table 3: TABLE 3 WSGR Docket No.57547-734.601 WSGR Docket No.57547-734.601 WSGR Docket No.57547-734.601 WSGR Docket No.57547-734.601 WSGR Docket No.57547-734.601 WSGR Docket No.57547-734.601 WSGR Docket No.57547-734.601 [00189] The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • the compounds described herein include all rotamers and “atropisomers as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritium, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavy isotopes such as deuterium, i.e., 2 H produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom.
  • one or more alkyl substituents in a compound disclosed herein has been replaced by deuteroalkyl substituents.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyn
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethane sulfonic acid, 1,
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (CI-C4 alkyl)4 hydroxide, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which can depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. As another example, “about” can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. With respect to biological systems or processes, the term “about” can mean within an order of magnitude, such as within 5-fold or within 2-fold of a value. Where particular values are described in the application and claims, unless otherwise stated, the term “about” means within an acceptable error range for the particular value.
  • the term “subject,” as used herein, generally refers to a vertebrate, such as a mammal (e.g., a human). Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets (e.g., a dog or a cat). Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
  • the subject is a patient, e.g., a human patient.
  • the subject is symptomatic with respect to a disease (e.g., cancer).
  • the subject is asymptomatic with respect to the disease. In some cases, the subject does not have the disease.
  • biological sample generally refers to a sample derived from or obtained from a subject, such as a mammal (e.g., a human).
  • Biological samples are contemplated to include but are not limited to, hair, fingernails, skin, sweat, tears, ocular fluids, nasal swab or nasopharyngeal wash, sputum, throat swab, saliva, mucus, blood, serum, plasma, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, earwax, oil, glandular secretions, bile, lymph, pus, microbiota, meconium, breast milk, bone marrow, bone, CNS tissue, cerebrospinal fluid, adipose tissue, synovial fluid, stool, gastric fluid, urine, semen, vaginal secretions, stomach, small intestine, large intestine, rectum, pancreas, liver, kidney
  • treating generally refers to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect.
  • the effect is prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or is therapeutic in terms of effecting a partial or complete cure for a disease and/or one or more symptoms of the disease.
  • Treatment may include treatment of a tumor in a mammal, particularly in a human, and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (e.g., including diseases that may be associated with or caused by a primary disease; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
  • Treating may refer to any indicia of success in the treatment or amelioration or prevention of a cancer, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease condition more tolerable to the patient; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating.
  • the treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of an examination by a physician.
  • treating includes the administration of the compounds or agents of the present invention to prevent or delay, to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with cancer or other diseases.
  • therapeutic effect refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject.
  • tumor or tumor cells
  • tumor cells generally refers to cells that grow and divide more than they should or do not die when they should.
  • tumor cells are present in a solid mass, such as a solid tumor, or in some cases, tumor cells are found in a non-solid form, such as in blood cancers.
  • Tumor or tumor cells also can include metastasis or metastasizing cells, where cancer cells break away from the original (primary) tumor and may form a new tumor in other organs or tissues of the body.
  • oncogene as used herein, generally refers to a gene that has the potential to cause cancer when inappropriately activated. In tumors or tumor cells, these genes are often mutated to remove negative regulatory domains or expressed at high levels.
  • ecDNA signature generally refers to one or more characteristics common to tumors or tumor cells that are ecDNA+.
  • the ecDNA signature is selected from the group consisting of a gene amplification; a p53 loss of function mutation; absence of microsatellite instability (MSI-H); a low level of PD-L1 expression; a low level of tumor inflammation signature (TIS); a low level of tumor mutational burden (TMB); an increased frequency of allele substitutions, insertions, or deletions (indels); and any combination thereof.
  • ecDNA signature includes a detection or identification of ecDNA using an imaging technology.
  • ecDNA signature does not include any imaging or direct detection of ecDNA.
  • selective ribonucleotide reductase inhibitor or “selective RNR inhibitor” as used interchangeably herein, generally refers to inhibitors of ribonucleotide reductase (RNR) that specifically inhibit RNR without inhibiting other proteins or enzymes.
  • RNR ribonucleotide reductase
  • the selective RNR inhibitor is not a nucleoside analog.
  • the selective RNR inhibitor is not gemcitabine.
  • the selective RNR inhibitor is not hydroxyurea.
  • the selective RNR inhibitor has better (improved) selectivity for RNR inhibition as compared to gemcitabine and/or hydroxyurea.
  • Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert- amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the
  • a numerical range such as “C 1 -C 6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C1-C10 alkyl.
  • the alkyl is a C1-C6 alkyl.
  • the alkyl is a C1-C5 alkyl.
  • the alkyl is a C1-C4 alkyl.
  • the alkyl is a C1-C3 alkyl.
  • an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.
  • alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include all isomers.
  • a numerical range such as “C2-C6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl).
  • Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl.
  • an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and/or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cyclo
  • the cycloalkyl is a 3 - to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered fully saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclofl.
  • cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -C00H, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2.
  • a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, bromomethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2- fluoropropyl, 1,2-dibromoethyl, 1 -chloroethyl, and the like.
  • Haloalkoxy refers to -O-haloalkyl, with haloalkyl as defined above.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. In some embodiments, 1-hydroxyeth-l-yl and 2-hydroxy-prop-2-yl, 2-hydroxy-2-methylprop-l-yl, or 2,3 -dihydroxypropyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium.
  • the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums.
  • Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, - CH2CH2OCH2CH2OCH3, -CH(CH 3 )OCH 3 , -CH 2 C(CH 3 )2OCH3, -CH2NHCH3, -CH 2 N(CH 3 )2, - CH(CH3)N(CH3)2, -CH2CH2NHCH3, or -CH 2 CH 2 N(CH3)2.
  • a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2.
  • a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. In some embodiments, the heterocycloalkyl comprises one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 folly saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 folly saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycl
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyr
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3 - to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3 - to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.
  • the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl is C-linked.
  • the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, ind
  • a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2.
  • the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, - CFHCHF2, etc ).
  • the term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.
  • Example A KRAS inhibition and ecDNA amplification
  • mice were implanted with CT26WT E3 G12C KRAS mutant tumor cells. Once tumors reached an average volume of 350 mm 3 , mice were started on vehicle only or the KRAS inhibitor (KRASi) adagrasib at 50 mg/kg orally once per day. Tumor growth over the course of the treatment is shown in FIG. 1. As a single agent, the KRASi resulted in a significant delay in tumor growth. However, at about day 14, the tumors began to exhibit resistance to the inhibitor and tumor growth resumed.
  • KRASi KRAS inhibitor
  • ecDNA counts were determined using FISH for murine KRAS and quantified by manual counts. As shown in FIG. 2, no KRAS amplified ecDNA was seen in vehicle treated or untreated tumors. In comparison, tumors that developed resistance to KRASi were associated with high levels of KRAS ecDNA at termination. Imaging of the FISH samples confirmed that the KRAS was amplified on ecDNA.
  • mice were implanted with CT26WT E3 G12C KRAS mutant tumor cells. Once tumors reached an average volume of 350 mm 3 , mice were started on one of the following therapeutic regimens using the KRAS inhibitor (KRASi) adagrasib and/or Compound 1: (1) vehicle only; (2) KRASi at 50 mg/kg orally once per day; (3) Compound 1 at 150 mg/kg subcutaneously every other day; or (4) Compound 1 at 150 mg/kg subcutaneously every other day + KRASi at 50 mg/kg orally once per day.
  • KRASi KRAS inhibitor
  • mice were treated with the KRAS inhibitor (KRASi) adagrasib at 50 mg/kg orally once per day to maintain ecDNA.
  • KRAS inhibitor KRAS inhibitor
  • adagrasib KRAS inhibitor adagrasib at 50 mg/kg orally once per day to maintain ecDNA.
  • mice were started on one of the following therapeutic regimens using KRAS inhibitor and/or Compound 1: (1) vehicle only; (2) KRASi at 50 mg/kg orally once per day; (3) Compound 1 at 50 mg/kg subcutaneously twice every other day; or (4) Compound 1 at 50 mg/kg subcutaneously twice every other day + KRASi at 50 mg/kg orally once per day.
  • Results are shown in FIG. 4.
  • the KRASi did not result in any delay in tumor growth demonstrating the adagrasib resistance.
  • Compound 1 either as a single agent or when combined with the KRASi resulted in significant tumor growth inhibition (>90%) on study day 12.
  • Mean tumor volume for Compound 1 treatments did not reach 500 mm 3 for all remaining tumors by Study Day 26, the last day of the study.
  • mice were implanted with WiDr V600E BRAF mutant tumor cells. Once tumors reached an average volume of -160 mm 3 , mice were started on one of the following therapeutic regimens using the EGFR antibody (cetuximab) and the BRAF inhibitor (encorafenib) and/or Compound 1: (1) vehicle only; (2) EGFR antibody at 20 mg/kg intraperitoneally twice per week and BRAFi at 20 mg/kg orally once per day; (3) Compound 1 at 30 mg/kg subcutaneously twice every other day; or (4) Compound 1 at 30 mg/kg subcutaneously twice every other day + EGFR antibody at 20 mg/kg intraperitoneally twice per week + BRAFi at 20 mg/kg orally once per day.
  • EGFR antibody cetuximab
  • BRAFi BRAFi
  • Results of tumor growth for each of the treatments is shown in FIG. 5.
  • EGFR antibody + BRAFi resulted in a significant delay in tumor growth for approximately 10 days; however, over the course of the study, the tumors began to exhibit resistance to the combination and continued to grow.
  • the median time for tumors in the double combination group to reach a tumor volume of 500 mm 3 was 43 days.
  • Compound 1 to the EGFR antibody + BRAFi combination, a significant increase on tumor growth inhibition was observed.
  • Example D Synthetic lethality of Compound 1 and pan-FGFR inhibition
  • mice were implanted with SNU-16 FGFR2 ecDNA+ tumor cells. Once tumors reached an average volume of -320 mm 3 , mice were started on one of the following therapeutic regimens using the FGFR inhibitor (infigratinib) and/or Compound 1: (1) vehicle only; (2) FGFRi at 15 mg/kg orally once per day; (3) Compound 1 at 30 mg/kg subcutaneously twice every other day, two weeks on / one week off; or (4) Compound 1 at 30 mg/kg subcutaneously twice every other day, two weeks on / one week off + FGFRi at 15 mg/kg orally once per day. [00242] Results of tumor growth for each of the treatments is shown in FIG.7.
  • FGFRi resulted in slight tumor regressions for approximately 10 days; however, over the course of the study, the tumors began to exhibit resistance and resumed growth. With the addition of Compound 1 to FGFRi, tumors regressed as on FGFRi alone; however, the mean tumor remained smaller than initial tumor volume for the duration of the study and a significant difference in mean tumor volume was observed at the end of study on Study Day 38.
  • Example E RNR Enzyme Activity
  • the plate layout included two validated reference compounds (Triapine (3-AP) and Hydroxyurea (HU)): • A dose response in duplicate; top concentration: 5 ⁇ M (3-AP) and 250 ⁇ M (HU), semi-log dilutions. • Spike wells in triplicate randomly spotted at four concentrations: o 250 ⁇ M, 100 ⁇ M, 30 ⁇ M and 2 ⁇ M for HU o 5 ⁇ M, 2 ⁇ M, 0.6 ⁇ M and 0.04 ⁇ M for 3-AP [00245] First, the multidrop pipes were saturated for 30 minutes with enzymatic solution. Then 30 ⁇ L of Stop solution was distributed in column 24. Next, 15 ⁇ L of enzyme was distributed in column 1 to 24.
  • Triapine (3-AP) and Hydroxyurea (HU) • A dose response in duplicate; top concentration: 5 ⁇ M (3-AP) and 250 ⁇ M (HU), semi-log dilutions. • Spike wells in triplicate randomly spotted at four concentrations: o 250
  • Example F Compound 1 treatment results in loss of ecDNA amplifications
  • SNU16 ecDNA+ cells were treated with Compound 1 at the IC50 and IC90 concentrations of 1.6uM and 2.4 uM for 15 days.
  • Cell viability was measured by a cell-death and viability assessment using Trypan Blue staining. Results are shown in FIG. 8A.
  • the treatments with Compound 1 led to a decline in cell viability.
  • a FISH based cytogenetic analysis of MYC and FGFR2 DNA of the SNU16 cells treated for 7 days at the IC90 concentration of Compound 1 showed a reduction in FGFR2 and MY C ecDNA levels as compared to the vehicle treated control. Results are shown in FIG. 8B.
  • SNU16 cells at both IC50 and IC90 concentrations of Compound 1 showed a reduction in ecDNA cargo oncoprotein expression of FGFR2 and, its post-translationally modified form pFGFR-T653/654, concomitant with elevated expression of replication stress, DNA-damage and cell death marker, including pCHKl-S345, gH2AX-S139, and cleaved-caspase 3-D175 (FIG. 8E).
  • pCHKl-S345, gH2AX-S139 cleaved-caspase 3-D175
  • Example G Compound 1 prevents ecDNA-mediated resistance associated with KRAS G12C inhibitor
  • Colorectal cancer non amplified CT26 cells were engineered to express the G12C allele of KRAS (CT26WT E3). The cells were then treated with adagrasib in a dose -dependent manner over weeks that led to acquired resistance to adagrasib mediated through the development of KRASG12C containing ecDNA as shown by FISH analysis (FIG. 9A). Resistance to adagrasib in this cell line was confirmed using a 5 -day cell proliferation assay. As shown in FIG. 9B, adagrasib treatment of the parental, CT26 SM5G72G non-amplified retained sensitivity to the compound, whereas the ecDNA+
  • KRASG12C amplified cells exhibited resistance to adagrasib. Activation of the KRAS and the flux through the KRAS pathway was assessed using western blotting.
  • the CT26 SM5G72G ecDNA+ KRASG12C amplified cells were found to harbor KRASG12C amplifications on the ecDNA in concomitance with the baseline activation of the MAPK signaling as shown by western blotting of relevant biomarkers (FIG. 9C).
  • a qPCR analysis was performed to assess KRASG12C gene copy number.
  • Example H Compound 1 delays the development of resistance to adagrasib in vivo
  • mice were implanted with CT26WT E3 G12C KRAS mutant tumor cells. Once tumors reached an average volume of 350 mm3 , mice were started on one of the following therapeutic regimens using KRAS inhibitor (adagrasib) and/or Compound 1: (1) vehicle only; (2) KRASi (adagrasib) at 50 mg/kg orally once per day (PO QD); (3) Compound 1 at 50 mg/kg subcutaneously twice every other day (SC BID Q2D); or (4) Compound 1 at 50 mg/kg subcutaneously twice every other day (SC BID Q2D) + KRASi (adagrasib) at 50 mg/kg orally once per day (PO QD). Results are shown in FIG. 10A.
  • adagrasib resulted in a significant delay in tumor growth.
  • the tumors began to exhibit resistance and tumor growth resumed.
  • qPCR analysis of genomic DNA isolated from tumors at termination demonstrated a significant increase in Kras gene copy number.
  • FIGS. 10A and 10B The Kras gene copy number determined in terminal tumors from the combination group demonstrated that Compound 1 abrogated adagrasib-mediated Kras amplification in resistant tumors (FIG. 10C).
  • Example I Compound 1 delays acquired resistance to treatment of MRTX1133 in Ct26 A '"' 4 ' l2l) CRC cells in vitro by arresting KRAS amplifications

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement comprenant l'administration d'un inhibiteur sélectif de la ribonucléotide réductase (RNR) en combinaison avec d'autres agents thérapeutiques, ce qui permet de traiter le cancer et de prévenir ou d'inverser la résistance aux agents thérapeutiques.
PCT/US2024/044534 2023-09-01 2024-08-29 Compositions de ribonucléotide réductase (rnr) et méthodes d'utilisation Pending WO2025049814A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363580096P 2023-09-01 2023-09-01
US63/580,096 2023-09-01
US202363589547P 2023-10-11 2023-10-11
US63/589,547 2023-10-11

Publications (2)

Publication Number Publication Date
WO2025049814A2 true WO2025049814A2 (fr) 2025-03-06
WO2025049814A3 WO2025049814A3 (fr) 2025-04-17

Family

ID=94820406

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/044534 Pending WO2025049814A2 (fr) 2023-09-01 2024-08-29 Compositions de ribonucléotide réductase (rnr) et méthodes d'utilisation

Country Status (1)

Country Link
WO (1) WO2025049814A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2021325905A1 (en) * 2020-08-12 2023-04-13 Boundless Bio, Inc. Replication stress pathway agent compositions and methods for treating cancer
IL311458A (en) * 2021-09-17 2024-05-01 Boundless Bio Inc Cyclic sulfonamide ribonucleotide reductase (rnr) inhibitors and uses thereof

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

Also Published As

Publication number Publication date
WO2025049814A3 (fr) 2025-04-17

Similar Documents

Publication Publication Date Title
WO2025049814A2 (fr) Compositions de ribonucléotide réductase (rnr) et méthodes d'utilisation
US12527790B2 (en) Checkpoint kinase 1 (CHK1) inhibitors and uses thereof
CN113454085B (zh) Mat2a的aza杂双环抑制剂和用于治疗癌症的方法
WO2024118564A1 (fr) Inhibiteurs de checkpoint kinase 1 (chk1) et leurs utilisations
WO2023230477A1 (fr) Inhibiteurs de la kinase 1 de point de contrôle (chk1) de pyridine et leurs utilisations
KR20150002730A (ko) 인간 히스톤 메틸트랜스퍼라제 ｅｚｈ２ 억제제의 염 형태
Gao et al. Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors
WO2022187200A1 (fr) Inhibiteurs de ribonucléotide réductase (rnr) et leurs utilisations
CN118434417A (zh) 环状磺酰胺核糖核苷酸还原酶(rnr)抑制剂及其用途
CA3217330A1 (fr) Inhibiteurs de pcna et inhibiteurs d'egfr pour le traitement du cancer
CN118488945A (zh) 磺酰胺核糖核苷酸还原酶(rnr)抑制剂及其用途
EP4626433A1 (fr) Combinaisons d'inhibiteurs de la checkpoint kinase 1 (chk1) et leurs utilisations
CN117777134B (zh) 作为mat2a抑制剂的多环类化合物
CN113164438B (zh) 治疗化疗难治性癌症的新联合用药方案
CN119176820A (zh) 作为mat2a抑制剂的三环类化合物
EP4698175A1 (fr) Inhibiteur de lysine acétyltransférase 6a (kat6a), associations et utilisations associées
US20260085067A1 (en) Cyclic sulfonamide ribonucleotide reductase (rnr) inhibitors and uses thereof
WO2024233766A1 (fr) Inhibiteurs d'ulk1/2 macrocycliques et leur utilisation
WO2021178857A1 (fr) Inhibiteurs de stat à substitution alpha et compositions de ceux-ci
KR20220072403A (ko) 포지오티닙 및 칼슘채널 억제제를 포함하는 암의 예방 또는 치료용 약학적 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24861080

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2024861080

Country of ref document: EP

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24861080

Country of ref document: EP

Kind code of ref document: A2