WO2020007106A1 - Utilisation médicale d'évofosfamide contre le cancer - Google Patents

Utilisation médicale d'évofosfamide contre le cancer Download PDF

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WO2020007106A1
WO2020007106A1 PCT/CN2019/084579 CN2019084579W WO2020007106A1 WO 2020007106 A1 WO2020007106 A1 WO 2020007106A1 CN 2019084579 W CN2019084579 W CN 2019084579W WO 2020007106 A1 WO2020007106 A1 WO 2020007106A1
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cancer
repair
tumor
inhibitors
xpf
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段建新
李安蓉
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Shenzhen Ascentawits Pharmaceutical Technology Co Ltd
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Shenzhen Ascentawits Pharmaceutical Technology Co Ltd
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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • TH-302 (Evofosfamide, cassol 918633-87-1) is a 2-nitroimidazole-induced hypoxia-activated prodrug (HAP) bromoisophosphoramide. Under hypoxic conditions, inactive TH-302 prodrugs can release highly toxic Br-IPM (shown in Structural Formula 1 below).
  • TH-302 has a broad spectrum of in vivo and in vitro biological activity, specific hypoxic selective activation activity, and induces H2AX phosphorylation and DNA cross-linking activity, which leads to cell cycle arrest. Therefore, this compound has been carried out by many pharmaceutical companies and research institutes. Development of anticancer drugs.
  • Cytochrome P450 oxidoreductase reduces TH-302 prodrug to obtain intermediate free radical anions, which are then unstable and decomposed into cytotoxic cytotoxin Br-IPM.
  • the key step of this step is the one-electron reduction process.
  • Studies have confirmed that the presence of oxygen can reverse the one-electron reduction process, that is, the presence of oxygen can hinder the one-electron reduction process, so the hypoxic environment can make TH-302 more Strong cytotoxicity.
  • a DNA repair mutant cell line based on Chinese hamster ovary cells was identified, and the cell line was determined to be a cell line lacking homology-dependent repair.
  • TH-302 has a highly sensitive growth inhibitory effect on cancer cells with specific gene mutations. That is to say, the above-mentioned hypoxic activation of TH-302 is only a manifestation.
  • cancer cells In other words, cancer cells with specific genetic mutations are more sensitive to TH-302, that is, TH-302 compounds have stronger proliferation inhibition and cell killing effects on cancer cells with specific genetic mutations, not just against Cancer cells in a hypoxic environment have stronger inhibitory effects.
  • cancer generally refers to all malignant tumors.
  • the patient's tumor or cancer tissue has at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN , Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7 , CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, L
  • the inclusion compound and the inclusion compound are specifically preferably a salt obtained by reacting an amine group in an imidazole ring in the molecule of efsexamine (TH-302) with an inorganic acid.
  • composition according to any one of claims 7-11, wherein the patient refers to human human beings patients and mammalian mammals patients other than humans.
  • the esofamide (TH-302) or the analog thereof according to any one of technical solutions 13-15 is used for treating tumors and cancers of patients with damaged DNA repair enzymes, wherein the tumors and cancers include:
  • esofomide or the analog thereof according to any one of technical solutions 13 to 16 is used for treating tumors and cancers with damaged DNA repair enzymes, wherein the analog refers to: Eff
  • the preparation containing efsoxamine (TH-302) or an analog thereof is used as a medicine for treating tumors and cancers of patients with damaged DNA repair enzymes, wherein the damaged DNA repair enzymes are
  • the preparation containing efsexamide (TH-302) or an analog thereof is used as a medicine for treating tumors and cancers of patients with impaired DNA repair, wherein
  • the preparation of somatamine (TH-302) or its analogs also contains other anticancer drugs and antitumor drugs.
  • Other anticancer drugs and antitumor drugs include HDAC inhibitors, estrogen receptor modulators, androgen receptor modulation.
  • Lung cancer non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma Basal cell carcinoma, adenocarcinoma, sweat adenocarcinoma, sebaceous adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, myeloid carcinoma, bronchial carcinoma, osteoblastoma, epithelial cancer, bile duct cancer, chorion Cancer, embryo cancer, seminoma, Wilms cancer, glioblastoma, astrocytoma, neuroblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, Vocal cord neuromas, meningiomas, neuroblast
  • the preparation containing esofomide (TH-302) or an analog thereof is used as a medicine for treating tumors and cancers with damaged DNA repair enzymes.
  • a method for treating tumors and cancers of patients with damaged DNA repair enzymes comprising administering to the patient suffering from the disease a pharmaceutical preparation containing efsoxamine (TH-302) or an analogue thereof, the patient
  • the tumor or cancer tissue has at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50 , MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2
  • One or more of the fanconi anemia pathway repair enzymes are damaged, preferably homologous recombination DNA repair homologous recombination damaged repair, nucleotide excision repair repair nucleotide damage repair, base excision repair repair Any one or more of the damages, more preferably homologous recombination DNA repair homologous recombination damage or homologous recombination DNA repair homologous recombination damage and nucleotide excision repair enzyme repair) damaged patients.
  • the treatment method according to any one of technical solutions 25-27, wherein the tumor and cancer include:
  • the combination therapy-free therapeutic drug according to any one of technical solutions 31-33, wherein the analog refers to a pharmaceutically acceptable salt, solvate, hydrate, stereo
  • the isomers and inclusion compounds are specifically preferably salts obtained by reacting an amine group in an imidazole ring in the molecule of efsexamine (TH-302) with an inorganic acid.
  • a method for treating patients with cancer or oncology first use BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54 , RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP , ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNALigase I, MMS19,
  • the patient's tumor or cancer tissue has at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175 , NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH , CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNA, Ligase I, MMS
  • the immunomodulatory drugs include immunosuppressive drugs and immune enhancing drugs.
  • Immunoenhancing drugs include: 1 non-specific active ingredients that enhance, regulate, and restore the body's immune response; 2 interferons or interferon inducers; 3 thymus hormones, thymus factors; 4 lymphokines, cytokines; 5 monoclonal antibodies and vaccines Conjugates; 6 reactivated immune-active cells; 7 tumor antigens and immune vaccines, 7 types of substances, specific drugs include thymosin, transfer factor, recombinant human interferon, pidotimod Pidotimod, BCG polysaccharide nucleic acid preparations And ginseng, astragalus, schisandra, medlar, codonopsis, cordyceps, ganoderma, and tremella polysaccharides have natural immune-enhancing effects.
  • a method for treating cancer or tumor comprising
  • the patient's tumor or cancer tissue has at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175 , NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH , CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNA, Ligase I, MMS
  • BRCA1, BRCA2, BARD1, FANCA RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, XRCC3, XRCC4 / XPF, XRCC1 / RCC, ERCC1 / RAD10, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, ERCC5 / XPG, KU80 mutations in one or more genes,
  • TMB Tumor mutation load (burden), that is, tumor gene mutation load
  • burden tumor gene mutation load
  • TMB Tumor mutation load (burden): It is generally believed that: TMB exceeds 20 mutations / Mb (Mb stands for every million bases), which is high; low At 10 mutations / Mb, it is low, and in the middle is middle.
  • CheckMate-032 This is a phase II clinical trial involving 401 patients with advanced lung cancer who have failed first-line treatment, receiving PD-1 inhibitors alone or in combination with ipimus.
  • the effective rate of the three groups among the people receiving combined therapy is 62%, 20%, and 23%, respectively.
  • the effective rate of the high TMB group is high. 3
  • the median overall survival of the three groups were: 22.0 months, 3.6 months, 3.4 months-22.0 months and 3.4 months, a difference of 6 times! The trial proved that for different cancer treatment drugs, different TMB levels have a great impact on the efficacy of the drug.
  • the present invention prefers the following genes: BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNALigas
  • the immunomodulatory drugs include immunosuppressive drugs and immune enhancing drugs.
  • Immunoenhancing drugs include: 1 non-specific active ingredients that enhance, regulate, and restore the body's immune response; 2 interferons or interferon inducers; 3 thymus hormones, thymus factors; 4 lymphokines, cytokines; 5 monoclonal antibodies and vaccines Conjugates; 6 reactivated immune-active cells; 7 tumor antigens and immune vaccines, 7 types of substances, specific drugs include thymosin, transfer factor, recombinant human interferon, pidotimod Pidotimod, BCG polysaccharide nucleic acid preparations And ginseng, astragalus, schisandra, medlar, codonopsis, cordyceps, ganoderma, and tremella polysaccharides have natural immune-enhancing effects.
  • the patient may be first administered with efsomide (TH-302) or an analogue thereof, and then administered with immunotherapy, or with efsexamide (TH-302) or an analogue thereof.
  • the method can be intravenous administration or intratumor administration.
  • Ku80 a gene encoding the Ku80 protein.
  • CDK7 12, Cyclin Dependent Kinase 7, 12 genes.
  • MNAT1, NAT1, CDK Activating Kinase Assembly Factor MNAT1, NAT1, CDK Activating Kinase Assembly Factor.
  • TFIIH Transcription Factor IIH gene.
  • FAAP20 Fanconi Anemia Core Complex Associated Protein 20.
  • RBBP8 RB BindingProtein 8, Endonuclease.
  • Flap endonuclease flanking endonuclease.
  • the specific treatment method for a disease is to first perform a genetic diagnosis test of the above genes on the subject or patient, that is, use the corresponding BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB
  • efsomide can treat a wide range of tumors and cancers, including but not limited to the following: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, Gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland Carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, myeloid carcinoma, bronchial carcinoma, osteoblastoma, epithelial cancer, bile duct cancer, chorionic carcinoma, embryo cancer, seminoma, cancer, Wilm Cancer, glioblastoma, astrocytoma, neuroblastoma, craniopharyngioma
  • the acid can be organic or inorganic acid, and the organic acid can be carboxylic acid (-COOH), sulfonic acid (-SO3H). , Sulfinic acid (RSOOH), thiocarboxylic acid (RCOSH), the inorganic acid is sulfuric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, etc., the present invention is preferably an inorganic acid;
  • TH-302 structures similar to those disclosed in CN105792845A, CN102161679A, CN102574866A, CN103458896A, CN1771043A, CN1791403A, CN101094838A, CN101501054A, CN1771334A, CN1738616A, CN1738629A, CN102746336A, CN103458880A, CN1917885A.
  • efsexamine TH-302
  • other anticancer or chemotherapeutic agents and immunotherapy drugs should also be able to achieve the purpose of the present invention and should also be protected.
  • Non-limiting examples of such agents can be found in Cancer Principles and Practice in Oncology, V.T. Devita and S. Hellman (editor), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Press. Those skilled in the art can identify which combination of agents can be used based on the specific characteristics of the drug and the cancer (or other indications) involved.
  • Combined anticancer agents used as a compound including but not limited to the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, microtubule inhibitors / stabilizers, extensions Naive isomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolites, antibodies or radioisotopes coupled to cytotoxic agents, HMG-CoA reductase inhibitors, isoprenyl transferase inhibitors, methods Protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitors, COX2 inhibitors, integrin blockers, PPAR agonists, MDR inhibitors and immunotherapeutics.
  • anticancer agents also include hypoxia-activatable agents, proteasome inhibitors, ubiquitin inhibitors, HDM2 inhibitors, TNF activators, BUB-R inhibitors, CENP-E inhibitors, and interferons (such as ⁇ -interferon ).
  • anticancer agents can be small molecules or biological agents (eg, RNA antisense agents and antibodies).
  • HDAC inhibitors are histone deacetylase inhibitors and include:
  • Fatty acids such as butyrate, phenyl butyrate and valproic acid
  • Cyclic peptides such as the natural products of the peptides FK-228, apicidin, and epoxyoxime;
  • Benzoamides such as MS-275, MGCD0103, etc.
  • estrogen receptor modulator refers to a compound that interferes with or inhibits estrogen binding to a receptor, regardless of mechanism.
  • examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, Idoxifene, LY353381, LY117081, toremifne, fulvestr Fulvestrant, anastrozole and letrazole.
  • Androgen receptor modulator refers to a compound that interferes with or inhibits androgen binding to a receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, Liarozole and abiraterone acetate.
  • microtubule inhibitors / microtubule stabilizing agents include paclitaxel, vinblastin sulfate, 3 ′, 4′-didehydro-4′-deoxy-8′-normal vinca leukocetin, thank you Docetaxel, vincristine, vinblastine, vinorelobine, rhizoxin, dolatatin, mivobulin, isethionate, auristatin ), Cemadotin, RPR109881, BMS184476, vinflunine, cryptocetin, 2, 3, 4, 5, 6-pentafluoro-N- (3-fluoroyl-4-methyl (Oxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valinyl-L-valinyl-N-methyl-L-valinyl-L-prolyl- L-proline-tert-butylamide, TDX258, epothilone (see US patents
  • Antimetabolite drugs include: 5-fluorouracil, enocitabine, carmofur, tegafur, pentostatin, doxifluridine, Trimetrexate, fludarabine, capecitabine, galocitabine, octosine ocfosfate, fosteabine ) Sodium Hydrate, Raltitrexed, Paltitrexid, Emitefur, Tiazofurin, Decitabine, Nolatrexed ), Pemetrexed, nelzarabine, 2′-deoxy-2′-methylenecytosine nucleoside, 2′-fluoromethylene-2′-deoxycytidine, N- [5- (2,3-dihydro-benzofuranyl) sulfonyl] -N '-(3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N2- [ 2 (E), 4 (E) -tetradecanedial
  • HMG-CoA reductase inhibitor refers to an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (see U.S. patents 4,231,938, 4,294,926, and 4,319,039), simvastatin (see U.S. patents 4,444,784, 4,820,850, and 4,916,239 ), Pravastatin (see U.S. patents 4,346,227, 4,537,859, 4,410,629, 5,030,447, and 5,180,589), fluvastatin (see U.S.
  • HMG-CoA reductase inhibitor includes all pharmaceutically acceptable lactone and acyclic acid forms (i.e., where the lactone ring is opened to form a free acid), as well as having HMG-CoA
  • lactone and acyclic acid forms i.e., where the lactone ring is opened to form a free acid
  • HMG-CoA The salt and ester forms of compounds having reductase inhibitory activity, and therefore the use of such salt, ester, open acid, and lactone forms is included within the scope of the present invention.
  • farnesyl protein transferase inhibitors examples include SARASARTM (4- [2- [4-[(11R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5 , 6] cycloheptan [1,2-b] pyridine-11-yl-]-1-piperidinyl] -2-oxoethyl] -1-piperidinecarboxamide, tipifarnib Wait.
  • angiogenesis inhibitor refers to a compound that inhibits the formation of new blood vessels, regardless of the mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosinase inhibitors, such as inhibitors of the tyrosinase receptors Flt-1 (VEGFR1) and Flk-1 / KDR (VEGFR2), epidermal-derived, fibroblasts Inhibitors of growth factors derived from platelets or derived from platelets, MMP (interstitial metalloproteinase) inhibitors, integrins blockers, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, These include non-steroidal anti-inflammatory agents (NSAIDs), such as aspirin and ibuprofen, and selective cyclooxygenase-2 inhibitors, such as celecoxib and rofecoxib.
  • NSAIDs non-steroidal anti-inflammatory agents
  • NSAIDs selective cyclooxygenase
  • kinase inhibitors include agents that inhibit a stepwise response of cell surface receptors to downstream information transduction of these surface receptors. This agent inhibits cell proliferation and survival.
  • agents that inhibit a stepwise response of cell surface receptors to downstream information transduction of these surface receptors This agent inhibits cell proliferation and survival.
  • EGFR e.g. gefitinib and erlotinib
  • antibodies to EGFR e.g. C225
  • inhibitors of ERB-2 e.g. trastuzumab
  • Inhibitors of IGFR inhibitors of cytokine receptors
  • inhibitors of MET inhibitors of PI3K
  • LY294002 serine / threonine kinases (including but not limited to inhibitors of Akt, for example in WO 02/083064, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf enzymes (e.g. BAY-43-9006), inhibitors of MEK (e.g. CI-1040 and PD- 098059), inhibitors of mTOR (such as Wyeth CCI-779), and inhibitors of C-ab1 kinase.
  • Other kinase inhibitors include those that inhibit proteins involved in cell circulation.
  • Aurora kinase inhibitors CDK inhibitors (such as flavonol, CYC202, BMS387032, and polar kinase inhibitors).
  • CDK inhibitors such as flavonol, CYC202, BMS387032, and polar kinase inhibitors.
  • agents that interfere with cell cycle checkpoints and pass to sensitize cancer cells to DNA damaging agents include, for example, inhibitors of ART, ATM, Chk1 and Chk2.
  • “Integrin blocker” refers to a compound that selectively antagonizes, inhibits, or neutralizes the binding of a physiological ligand to ⁇ v ⁇ 3 integrin, and selectively antagonizes, inhibits, or neutralizes the binding of a physiological ligand to ⁇ v ⁇ 5 Integrin compounds that antagonize, inhibit, or neutralize the binding of physiological ligands to both ⁇ v ⁇ 3 integrin and ⁇ v ⁇ 5 integrin, and that antagonize, inhibit, or neutralize specific proteins expressed on microvascular endothelial cells Integrin active compound.
  • Combinations with compounds other than anticancer compounds are also encompassed by the methods of the invention.
  • the combination of efsomide (TH-302) or its analogues with PPAR- ⁇ (i.e., PPAR-gamma) agonist and PPAR- ⁇ (i.e., PPAR-delta) agonist can be used to treat certain malignant conditions.
  • PPAR- ⁇ and PPAR- ⁇ are nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ , respectively.
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis have been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31: 909-913; J.
  • Evesomide (TH-302) or its analogues can also be administered in combination with one or more inhibitors of inherent multidrug resistance (MDR), especially MDR associated with high-level transporter protein performance.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853, and PSC833 (valspodar).
  • anticancer agents also include hypoxia-activatable agents (e.g. tirapazamine), proteasome inhibitors (e.g. lactate and bortezomib), ubiquitin inhibitors, HDM2 inhibitors , TNF activator, BUB-R inhibitor, CENP-E inhibitor and interferon alpha.
  • hypoxia-activatable agents e.g. tirapazamine
  • proteasome inhibitors e.g. lactate and bortezomib
  • ubiquitin inhibitors e.g. lactate and bortezomib
  • HDM2 inhibitors e.g. TNF activator
  • BUB-R inhibitor e.g., BUB-R inhibitor
  • CENP-E inhibitor interferon alpha.
  • the design principle of chemotherapy / immunotherapy is to first use DNA damaging agents (chemotherapeutics) to enhance the immune activity of cancer cells, and then use immunotherapy, which will greatly increase the anti-cancer effect of immunotherapy.
  • DNA damaging agents chemotherapeutics
  • it is essential to select a DNA damaging agent with an immune up-regulation function.
  • ICD immune-active cell death
  • TAE tumor microenvironment
  • Evsoxamine induces more DNA damage (existing experimental evidence indicates that homologous recombination repair is damaged, nucleotide excision repair is damaged, Impaired nonhomologous endjoining, impaired base excision repair, impaired mismatch repair, impaired repair of fanconi anemia pathway due to impaired repair defects
  • TH-302 Evsoxamine
  • TIL tumor infiltrating lymphocytes
  • the combination of efsomide (TH-302) and immunotherapy can more effectively treat damaged homologous recombination repair, damaged nucleotide excision repair, non-identical repair Cancer patients with nonhomologous endjoining, base excision repair, impaired mismatch repair, and impaired fanconi anemia pathway repair enzymes.
  • Immunotherapy drugs include immune checkpoint inhibitors such as PD-1 inhibitors (such as Keytruda), PD-L1 inhibitors (such as Tecentriq, Imfinzi) and CTLA4 inhibitors (such as Yervoy).
  • PD-1 inhibitors such as Keytruda
  • PD-L1 inhibitors such as Tecentriq, Imfinzi
  • CTLA4 inhibitors such as Yervoy
  • efsomide TH-302
  • the cells are at least BRCA1 and BRCA2.
  • Figure 1 shows the in vitro proliferation curve of H460 cells under different oxygen concentrations and different TH-302 concentrations
  • Figure 2 is an in vitro proliferation curve of H460 cells under different concentrations of TH-302 at 0.1% oxygen concentration
  • Figure 3 shows the results of the IC50 test of H460 cells' proliferation inhibition activity in vitro at different drug exposure times under different oxygen concentrations and different TH-302 concentrations;
  • Figure 4 shows the cytotoxicity results of human cancer cell lines after being exposed to TH-302 drug for 2 hours under N2 or air, and then incubating in air for 3 days.
  • Cells were seeded 24 hours before starting treatment. The cells were then incubated with the drug at the prescribed oxygen concentration for 2 hours. At the end of the treatment, the washed cells were plated and placed in an incubator for 10 days.
  • VC-8, UWB1.289 and FANCA strains cells were plated in triplicate in 6-well plastic plates of 500 to 1,000 cells per well and processed.
  • TH-302 was cultured under hypoxic conditions for 48 hours, and then continuously cultured for about 10 days in a drug-free medium under normoxic cattle. Cells were counted with crystal violet and colony staining over 50 cells.
  • TH-302 cytotoxic activity increased with decreasing oxygen levels.
  • hypoxia has a time-dependent selective activation of TH-302, and longer drug exposure produces more TH-302 toxins.
  • the relationship between TH-302 toxin concentration production and exposure time is nearly linear.
  • TH-302 has the highest activity in the case of very severe hypoxia ( ⁇ 0.1% O2), which greatly reduces the toxicity of the drug in vivo under normal oxygen.
  • TH-302 has a low cytotoxic effect under normoxic conditions with IC50 values greater than 40umol / L. Cytotoxicity increased significantly in all 32 cell lines under hypoxic conditions.
  • the normoxic / hypoxic toxicity ratio (IC50 ratio) can be up to 600 times (see reference 2: Meng F, Evans J W, Bhupathi D, et al. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. [ J]. Molecular Cancer Therapeutics, 2012, 11 (3): 740 Table 1 on page 744).
  • Chinese hamster ovary cell-based DNA to repair the cells of the defective cell line (Tables 1 and 2): the test was carried out and found that XRCC1, ERCC4 / XPF, ERCC5 / XPG, XRCC3, Ku-80 (cancer) cells with mutation and damage are more sensitive to TH-302 compound.
  • Table 2 Comparison results of increased sensitivity of TH-302 cells deficient in homologous recombination DNA repair enzymes.
  • HCR hypoxia cytotoxicity ratio
  • hypoxic cytotoxicity ratio which is the ratio of the cell activity IC50 value of air air to the cell activity IC50 value of N2 nitrogen.
  • Table 3 Homologous recombination DNA repair of damaged BRCA1, BRCA2 and FANCA-deficient cell lines has increased sensitivity to TH-302, and-/-indicates a defect.
  • TH-302 is more sensitive to (cancer) cells with specific gene locus mutations that cause damage. It has stronger killing and inhibitory activities, that is, TH-302 has specific targeted killing and inhibitory effects on (cancer) cells with specific gene locus mutations that cause damage.
  • UV41 cell line is a cell with nucleotide excision repair enzyme deficiency compared to AA8. It is sensitive to large-volume adduct mutants and belongs to excision repair supplement group 4. UV41 is a DNA cross-linking agent. Extremely sensitive (see [1] Thompson LH, et.Repair of DNAadducts, asynchronous, CHO cells, and the role of repair in cell, killing, and mutation induction, synchronizing, synchronizing, and dealing with 7-bromomethylbenzMol.Somatic.
  • Damage to DNA repair enzymes in UV41 cells can cause BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNA, Ligase I, MMS19, MNAT1,
  • EM9 is a repair-deficient mutant derived from AA 8 (see ATCC CRL-1859). This cell line was selected to enhance sensitivity to ethyl mesylate (EMS). This cell line has defects in DNA single-strand break repair. The baseline frequency of sister chromatid exchange is 10 times higher than AA8 before mutation, and its sensitivity to X-ray killing is 2 times higher than that of AA8 cells. The defect was corrected by the human XRCC1 gene.
  • Damage to DNA repair enzymes in EM9 cells may cause BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNA, Ligase I, MMS19, MNAT
  • TH-302 has a selective inhibitory effect on EM9 cells after genetic mutations in normal AA8 cells and AA8 cells: HCR value reaches 25 under hypoxic N2 conditions and air conditions, and TH-302 302 has selective inhibitory effect on cancer cells with the above-mentioned gene mutation.
  • UV135 cell line is a cell with nucleotide excision repair enzyme deficiency compared to AA8. It is sensitive to large-volume adduct mutants and belongs to the excision repair supplement group 5
  • Damage to DNA repair enzymes in UV135 cells can cause BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNA, Ligase I, MMS19, MNAT
  • TH-302 has a selective inhibitory effect on normal AA8 cells and AA8 cells after genetic mutation of UV135 cells: HCR value reaches 25 under hypoxic N2 conditions and air conditions, and TH-302 302 has selective inhibitory effect on cancer cells with the above-mentioned gene mutation.
  • the irs1SF cell line is a derivative of the CHO-AA8 cell line and is an X-ray repair cross-complement-complementing gene 3 (XRCC3) for repairing damaged cell lines.
  • XRCC3 X-ray repair cross-complement-complementing gene 3
  • Damage to the DNA repair enzyme of irs1SF cells can cause BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNA, Ligase I, MMS19
  • TH-302 has selective inhibitory effect on irs1SF cells after genetic mutations in normal AA8 cells and AA8 cells: HCR value reached 167 under hypoxic N2 conditions and air conditions, and TH-302 302 has selective inhibitory effect on cancer cells with the above-mentioned gene mutation.
  • xrs5 is an X-ray sensitive Chinese hamster ovarian mutant cell line that is derived from CHO-K1 cells by treating the cells with ethyl methanesulfonate and growing in agar. These cells belong to X-ray complementary group 5 (XRCC5) and are mutants in the p86 subunit of Ku autoantigen. Ku has been shown to be involved in DNA double-strand break repair and V (D) J recombination. After treatment with azacytidine, cells will revert to wild type (see [1] Jeggo PA, Kemp LM. X-ray-sensitive mutations of Chinese Hamsterovary cells.
  • Damaged DNA repair enzymes in XRS5 cells can cause BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC8 / CSA, LIG1 / DNA, Ligase I, MMS19, M
  • TH-302 has a selective inhibitory effect on XRS5 cells after genetic mutation in normal CHO-K1 cells and CHO-K1 cells: for XRS5 after genetic mutation, its IC50 value is lower, that is, TH -302 has a selective inhibitory effect on cancer cells having the above-mentioned gene mutation.
  • UWB1-BRCA1 + / + cells that is, UWB1.289 + BRCA1 ( CRL-2946 TM ), UWB1.289 + BRCA 1 is a stable cell line derived from UWB1.289 (ATCC CRL-2945), which is a human ovarian cancer line positive for BRCA1 gene.
  • BRCA1 was positive
  • cytokeratin 7 (CK-7) was positive
  • calcium-binding protein was positive
  • WT Wilms' tumor protein
  • the pcDNA3 plasmid carrying wild-type BRCA1 was transfected into the parental line. Restoring wild-type BRCA1 function in these cells partially restored the DNA damage response.
  • UWB1-BRCA1-/-cells that is, UWB1.289 ( CRL-2945 TM ), a BRCA1-deleted human ovarian cancer cell line UWB1.289, a tumor derived from papillary serous histology. Ovarian cancer is the most common form. Cytokeratin 7 (CK-7) was positive, calcium-binding protein was positive, Wilms' tumor protein (WT) was positive, BRCA1 was negative and deleted. The BRCA1-deleted human ovarian cancer cell line UWB1.289 comes from a papillary serous histological tumor, and ovarian cancer is the most common form.
  • UWB1.289 carries a germline BRCA1 mutation in exon 11 and has a deletion of the wild-type allele. It is negative for estrogen and progesterone receptors and has acquired somatic mutations in p53. It is sensitive to ionizing radiation.
  • TH-302 has a selective inhibitory effect on normal wild-type VC-8-BRCA2 + / + cells and BRCA2-deleted VC-8-BRCA2-/-cells: after BRCA-2 gene deletion Cells have a lower IC50 value, that is, TH-302 has a selective inhibitory effect on cancer cells with the above-mentioned BRCA2 deletion.
  • TH-302 has a specific inhibitory effect on cells with specific genetic mutations, specifically cells with damaged DNA repair enzymes.
  • the cells are at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR , CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MRE11, p53, NBS1, XRS2, XRCC2, XRCC3, XRCC4 / XPF, ERCC1, ERCC2 / XPD, ERCC3 / XPB, ERCC4 / XPF, XRCC1, Ku80, MHS6, MGMT, PARP, ERCC5 / XPG, CCNH, CDK7, CETN2, DDB1, DDB2, ERCC5 / XPG, ERCC6 / CSB, ERCC

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Abstract

L'évofosfamide (TH-302), ou un analogue de celui-ci, présente un effet inhibiteur spécifique sur une cellule présentant une mutation génétique spécifique, en particulier sur une cellule lésée quant à la réparation de l'ADN. La cellule ou le tissu présente au moins une ou plusieurs mutations génétiques dans les BRCA1, BRCA2, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MER11, p53, NBS1, XRS2, XRCC2, XRCC3, ERCC1, ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP et ERCC5. À cet effet, l'invention concerne une utilisation médicale de l'évofosfamide (TH-302), ou d'un analogue de celui-ci, dans le traitement de tumeurs ou d'un cancer chez un patient atteint d'un cancer présentant une ou plusieurs des mutations génétiques spécifiques.
PCT/CN2019/084579 2018-07-05 2019-04-26 Utilisation médicale d'évofosfamide contre le cancer Ceased WO2020007106A1 (fr)

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WO2023025291A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Solution de formulation lyophilisée, formulation lyophilisée, procédé et utilisation associés
WO2023025312A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Patient résistant aux inhibiteurs de parp traités avec th-302
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WO2023198188A1 (fr) 2022-04-15 2023-10-19 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer faisant appel à th-302 seul ou en association avec un inhibiteur de parp
WO2023226959A1 (fr) 2022-05-23 2023-11-30 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer par combinaison d'un promédicament d'agent alkylant et d'un inhibiteur de cycle cellulaire
WO2024061346A1 (fr) 2022-09-22 2024-03-28 深圳艾欣达伟医药科技有限公司 Utilisation d'un composé activé par hypoxie dans la préparation d'un médicament pour le traitement d'un patient atteint d'un cancer
WO2025026214A1 (fr) 2023-07-28 2025-02-06 深圳艾欣达伟医药科技有限公司 Traitement de la mutation du gène p53 ou de patients atteints d'un cancer négatif et d'une tumeur
EP4674418A1 (fr) 2023-02-27 2026-01-07 Ascentawits Pharmaceuticals, Ltd. Solution, formulation lyophilisée, emballage unitaire de formulation lyophilisée, injection et procédé de préparation d'injection

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Publication number Priority date Publication date Assignee Title
WO2023025291A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Solution de formulation lyophilisée, formulation lyophilisée, procédé et utilisation associés
WO2023025312A1 (fr) 2021-08-27 2023-03-02 深圳艾欣达伟医药科技有限公司 Patient résistant aux inhibiteurs de parp traités avec th-302
WO2023174319A1 (fr) 2022-03-15 2023-09-21 深圳艾欣达伟医药科技有限公司 Méthode de traitement d'un patient atteint d'un cancer à mutation de brca
EP4494643A4 (fr) * 2022-03-15 2025-09-10 Ascentawits Pharmaceuticals Ltd Méthode de traitement d'un patient atteint d'un cancer à mutation de brca
WO2023198188A1 (fr) 2022-04-15 2023-10-19 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer faisant appel à th-302 seul ou en association avec un inhibiteur de parp
WO2023226959A1 (fr) 2022-05-23 2023-11-30 深圳艾欣达伟医药科技有限公司 Méthode de traitement du cancer par combinaison d'un promédicament d'agent alkylant et d'un inhibiteur de cycle cellulaire
EP4529926A1 (fr) 2022-05-23 2025-04-02 Ascentawits Pharmaceuticals, Ltd. Méthode de traitement du cancer par combinaison d'un promédicament d'agent alkylant et d'un inhibiteur de cycle cellulaire
WO2024061346A1 (fr) 2022-09-22 2024-03-28 深圳艾欣达伟医药科技有限公司 Utilisation d'un composé activé par hypoxie dans la préparation d'un médicament pour le traitement d'un patient atteint d'un cancer
EP4674418A1 (fr) 2023-02-27 2026-01-07 Ascentawits Pharmaceuticals, Ltd. Solution, formulation lyophilisée, emballage unitaire de formulation lyophilisée, injection et procédé de préparation d'injection
WO2025026214A1 (fr) 2023-07-28 2025-02-06 深圳艾欣达伟医药科技有限公司 Traitement de la mutation du gène p53 ou de patients atteints d'un cancer négatif et d'une tumeur

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