EP4619106A2 - Traitement de cancers dépendants de l'asct2 - Google Patents

Traitement de cancers dépendants de l'asct2

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Publication number
EP4619106A2
EP4619106A2 EP23892424.5A EP23892424A EP4619106A2 EP 4619106 A2 EP4619106 A2 EP 4619106A2 EP 23892424 A EP23892424 A EP 23892424A EP 4619106 A2 EP4619106 A2 EP 4619106A2
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EP
European Patent Office
Prior art keywords
oxo
dimethyl
phenanthren
pyran
optionally substituted
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.)
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EP23892424.5A
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German (de)
English (en)
Inventor
Xiangping Qian
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Neupharma Inc
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Neupharma Inc
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Publication of EP4619106A2 publication Critical patent/EP4619106A2/fr
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin

Definitions

  • the present disclosure generally relates to the fields of chemistry, biology, and medicine.
  • the present disclosure describes methods for the treatment of ASCT2-dependent cancers using Na + /K + -ATPase inhibitors.
  • Cancer can be viewed as a breakdown in the communication between tumor cells and their environment, including their normal neighboring cells. Signals, both growth-stimulatory and growth-inhibitory, are routinely exchanged between cells within a tissue. Normally, cells do not divide in the absence of stimulatory signals, and likewise, will cease dividing in the presence of inhibitory signals. In a cancerous, or neoplastic state, a cell acquires the ability to “override” these signals and to proliferate under conditions in which normal cells would not grow.
  • Cardiotonic steroids like digoxin and digitoxin are a class of naturally derived compounds that bind to and inhibit Na + /K + -ATPase (sodium pump). Members of this family have been used for the treatment of heart failure and arrhythmia for many years. Recent findings have revealed that these compounds may be involved in the regulation of several important cellular processes. Several cardiotonic steroids such as digitoxin and oleandrin have shown inhibitory effect on the growth of human tumor cells.
  • the present disclosure provides methods of treating or preventing a cancer associated with elevated ASCT2 expression in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a Na + /K + -ATPase (NKA) inhibitor.
  • a Na + /K + -ATPase (NKA) inhibitor a Na + /K + -ATPase (NKA) inhibitor.
  • the present disclosure provides methods of treating a cancer associated with dysregulated glutamine metabolism in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.
  • the present disclosure provides methods of stabilizing or reducing the volume of a solid tumor of a cancer associated with elevated ASCT2 expression in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.
  • the present disclosure provides methods of reducing the volume of a solid tumor of a cancer associated with elevated ASCT2 expression in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an NKA inhibitor. In some aspects, the present disclosure provides methods of modulating the concentration of one or more biomarkers of a cancer associated with elevated ASCT2 expression in a cell comprising contacting the cell with an NKA inhibitor.
  • the present disclosure provides methods of suppressing ASCT2 protein expression in a cell comprising contacting the cell with an NKA inhibitor.
  • the present disclosure provides methods of reducing the rate of proliferation of a cancer cell comprising contacting the cell with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression.
  • the NKA inhibitor is a bufadienolide derivative, or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound of formula (I): wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; and
  • Ri, R2, R3, R4, R5, Re, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or
  • Ri and R2, or R5 and Re, or R7 and Rs, or R9 and Rio, or Rn and R12 mutually independently, together in each case denote an oxo group ( 0); or R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
  • Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
  • R13 is selected from hydrogen, optionally substituted alkyl, and formyl
  • Li is selected from a covalent bond, *-C(O)O-, *-[C(R a )(Rb)]s-O-, and *-[C(R a )(Rb)]s- C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein: R a and Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • R a and Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; or
  • R15 and one occurrence of R3 are together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Z is selected from -OR14 and -NR15R16, wherein:
  • R17 and Ris are independently selected from hydrogen and optionally substituted alkyl
  • Ris is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and Ri6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are
  • R15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Wi is selected from the following moi eties: wherein: m is selected from 0, 1, 2, and 3;
  • Y is selected from O and NR24;
  • R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl; R.24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substitute
  • W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.
  • FIG. 1A-1D shows the effect of RX108 on Na + /K + -ATPase activity and human HCC cell proliferation in vitro and tumorigenesis in a xenograft mouse model.
  • the chemical structure of RX108 (FIG. 1A) and its inhibitory activity against Na + /K + -ATPase (FIG. IB).
  • the percent suppression of Huh7 (FIG. 1 C 1), Hep3B (FIG. 1C2), and LO2 (FIG. 1C3) cell growth in culture after exposure to different doses of RX108 for different times as indicated.
  • Tumor growth curve (FIG. ID 1 ) and tumor weights (FIG. 1D2) for Huh7 xenografts in nude mice after treatment with different doses of RX108 (n 10/group).
  • the data are presented as mean ( ⁇ SD) values. ** p ⁇ 0.01 versus control.
  • FIG. 2A & 2B show Annexin V-fluorescein isothiocyanate/PI double staining and flow cytometric analysis of HCC cells treated with RX108.
  • Hep3B cells exposed to different doses of RX108 for 48 h were subjected to Annexin V-fluorescein isothiocyanate/PI double staining followed by flow cytometry.
  • FIG. 2A The differences in the percentages of PI7Annexin-V + , PI + / Annexin- V + , PI + / Annexin- V, and PI7Annexin-V cells after treated with RX108.
  • FIG. 2B Representative histograms of Hep3B cells treated with vehicle control or RX108. The data are presented as mean ( ⁇ SD) values.
  • FIG. 3A & 3B show the effect of RX108 on HCC cell metabolism.
  • the data are presented as mean ( ⁇ SE) values.
  • FIG. 4A-4G show the effect of RX108 on energy metabolism in Hep3B and Huh7 cells.
  • Hep3B cells were treated with RX108 and incubated with a medium containing 13 Cs- and 15 N2- glutamine or 13 Ce-glucose at 37 °C for 24 h. Afterward, cell samples were harvested for ion chromatography -MS analysis.
  • FIG. 4E Cellular NADH (FIG. 4E) and NADPH (FIG. 4F) concentrations in Hep3B cells and Huh7 cells after the cells were treated with RX108 for 2 h.
  • FIG. 4G Oxygen Consumption Rate (OCR) levels in Huh7 cells treated with RX108 measured using a Seahorse mitochondrial stress test and normalized to cell number.
  • NP RX108.
  • the data are presented as mean ( ⁇ SD) values. *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; ****p ⁇ 0.0001. [017] FIG.
  • FIG. 5A-5D show the effect of ASCT2 on RX-108 elicited antiproliferative activity in HCC cells and overall survival of HCC patients.
  • Western blot analysis (FIG. 5A1) and quantification (FIG. 5A2) of ASCT2 protein expression in Hep3B cells after exposure to RX108 for 48 h.
  • ASCT2 siRNA transfection downregulated ASCT2 protein expression in Hep3B cells (FIG. 5B1 & 5B2) and drastically reduced Hep3B cell growth as determined according to the total cell number or viable cell count (FIG. 5B3 & 5B4).
  • HCC cell addiction to glutamine for proliferation the growth of Huh7 (FIG. 5C1) and Hep3B (FIG. 5C2) cells after treatment with a medium containing 0.2 mM or 2 mM glutamine for 24, 48, 72, and 96 h.
  • the data are presented as mean ( ⁇ SD) values. *** p ⁇ 0.001; **** p ⁇ 0.0001 versus control.
  • the survival data of HCC patients were extracted from public available database as indicated (FIG.
  • 5D1 the human protein atlas: https://www.proteinatlas.org/ENSG00000105281- SLClA5/pathology/liver+cancer; cBioPortal for Cancer Genomics: FIG. 5D2, TCGA, PanCancer Atlas, and FIG. 5D3, TCGA liver hepatocellular Carcinoma, with source data from GDAC Firehose).
  • FIG. 6A-6D show the effect of RX108 on protein expression and glutamine metabolism in xenograft model.
  • Immunohistochemical analysis of ASCT2 (FIG. 6A1, representative staining image; FIG. 6A2, quantitative staining data), Ki67 (FIG. 6B1, representative staining image; FIG. 6B2, quantitative staining data), and cleaved caspase 3 (FIG. 6C1, representative staining image; FIG. 6C2, quantitative staining data) in huh7 cells xenograft tumors after RX108 exposure.
  • FIG. 6D LC-MS/MS measurement of the concentration of glutamine metabolites in the same tumor samples. The data are presented as mean ( ⁇ SD) values. *p ⁇ 0.05 vs. control.
  • HCC human hepatocellular carcinoma
  • ASCT2 alanine serine cysteine transporter 2
  • HCC Hepatocellular carcinoma
  • Liver cancer is the fourth most common cause of cancer-related deaths and ranks sixth in terms of cancer incidence worldwide.
  • liver cancer is the second most lethal tumor, and its incidence has tripled since 1980 (Siegel et al., 2019; Villanueva, 2019).
  • Surgical resection at an early stage is the only curative treatment option, but more than 80% of HCCs are diagnosed at an advanced stage with inoperable distant metastases (Yang and Roberts, 2010).
  • Patients with unresectable HCC can benefit from multimodality treatment options, including percutaneous ethanol injection, radiofrequency ablation, and magnetic resonance-guided laser thermal ablation (Villanueva, 2019; Slotta et al., 2015).
  • HCC cells exhibit an oncogenetically driven addiction to the neutral amino acid glutamine, which is used as a carbon and nitrogen source for protein and nucleotide synthesis and a substrate for energy production, cell signaling, and oxidative protection (Schulte et al.,
  • Sorafenib-resistant HCC cells exhibited much higher glutamine metabolic activity than did nonresistant cells regulated by peroxisome proliferator-activated receptor G (Kim et al., 2017). Rapidly proliferating cancer cells consume glutamine at a dramatically greater rate than do normal cells (Wang et al., 2018), and this consumption is fueled by elevated expression of glutamine transporters such as Na + -dependent alanine serine cysteine transporter 2 (ASCT2/SLC1 A5). Authors reported that ASCT2 was upregulated in HCC cells and that this upregulation was inversely associated with survival (Sun et al., 2016).
  • ASCT2 inhibitors have been developed or tested in vitro and in preclinical animal models and demonstrated antitumor activity, including glutamine analogs (Esslinger et al., 2005; Schulte et al., 2016), V-9302 (a competitive small-molecule antagonist of transmembrane glutamine flux; Schulte et al., 2018), and ASCT2-blocking antibodies (Osanai-Sasakawa et al. ,2018; Kasai et al., 2017).
  • glutamine analogs Esslinger et al., 2005; Schulte et al., 2016
  • V-9302 a competitive small-molecule antagonist of transmembrane glutamine flux
  • ASCT2-blocking antibodies Olesanai-Sasakawa et al. ,2018; Kasai et al., 2017.
  • the amino acid analogs and V- 9302 are not suitable for specific targeting of glutamine addiction via ASCT2 in tumor cells.
  • MEDI7247 an ASCT2-blocking antibody conjugated with the toxic drug pyrrolobenzodiazepine
  • NCT03106428 relapsed/refractory hematological malignancies
  • NCT03811652 advanced or metastatic solid tumors, including lung, head and neck, pancreatic, colorectal, and prostate cancers
  • HCC remains a global medical burden with a rising incidence and has a dismal prognosis, largely due to a lack of early detection methods and effective therapeutic modalities. Efforts to improve the outcomes of patients with HCC depend on a thorough understanding of the molecular pathogenesis of this tumor and the development of mechanism-based drugs to treat it.
  • the major function of the liver is whole-body metabolism regulation, in which it orchestrates the clearance of toxins; balances glucose, lipid, and amino acid uptake; and maintains metabolic homeostasis.
  • Elevated ASCT2 is a prognostic marker for HCC (Sun et al., 2016), and the different levels of ASCT2 expression in cancer and normal cells makes targeting overexpressed ASCT2 a promising approach for cancer therapy (Wahi and Holst, 2019; Broer, 2018).
  • Different ASCT2 inhibitors are being developed and tested but have yet to be applied clinically (Schulte et al., 2018; Broer et al., 2018; Ndaru et al., 2019).
  • advances in structural characterization of substrate recognition by ASCT2 will greatly facilitate the development of new specific ASCT2 inhibitors (Scopelliti et al., 2018).
  • ASCT2 is an epidermal growth factor receptor (EGFR)-associated protein and that targeting EGFR by cetuximab led to downregulation of ASCT2 in an EGFR expression-dependent manner via cetuximab-mediated EGFR endocytosis (Lu et al., 2016).
  • EGFR epidermal growth factor receptor
  • RX108 has antiproliferative effects in both HCC cells and relevant xenograft HCC model by inducing apoptosis and reducing glutamine metabolism by downregulating glutamine transporter expression and function in tumors.
  • the present disclosure provides several lines of evidence supporting the use of a Na + /K + -ATPase (NKA) inhibitor, such as RX108, to target a subgroup of HCCs with dysregulated glutamine metabolism.
  • a Na + /K + -ATPase (NKA) inhibitor such as RX108
  • the use of a Na + /K + -ATPase (NKA) inhibitor impairs glutamine metabolism and is a potential therapy for patients with HCC whose tumors have high levels of ASCT2 expression and glutamine dependent.
  • a Na + /K + -ATPase (NKA) inhibitor such as RX108
  • the use of a Na + /K + -ATPase (NKA) inhibitor such as RX108, inhibits HCC cell proliferation in vitro.
  • the use of a Na + /K + -ATPase (NKA) inhibitor such as RX108, inhibits tumorigenesis in vivo.
  • the inhibition of tumorigenesis is accompanied by significant induction of apoptosis.
  • the use of a Na + /K + -ATPase (NKA) inhibitor, such as RX108 significantly downregulates ASCT2, the transporter of glutamine, in HCC cells.
  • the use of a Na + /K + -ATPase (NKA) inhibitor, such as RX108 reduces glutamine and its metabolite concentrations in HCC cells and tumors
  • the use of a Na + /K + -ATPase (NKA) inhibitor, such as RX108 inhibits the energy metabolic pathway in HCC cells.
  • HCC cells are addicted to glutamine for proliferation, knockdown of ASCT2 drastically reduced HCC cell growth, and the antitumor effect of a Na + /K + -ATPase (NKA) inhibitor, such as RX108, is dependent on glutamine transport.
  • a high level of ASCT2 mRNA expression in human HCC is associated with unfavorable survival.
  • the present disclosure provides methods of treating or preventing a cancer associated with elevated ASCT2 expression in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a Na + /K + -ATPase (NKA) inhibitor.
  • a Na + /K + -ATPase (NKA) inhibitor a Na + /K + -ATPase (NKA) inhibitor.
  • the present disclosure provides methods of treating a cancer associated with dysregulated glutamine metabolism in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.
  • the present disclosure provides methods of stabilizing or reducing the volume of a solid tumor of a cancer associated with elevated ASCT2 expression in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.
  • the present disclosure provides methods of reducing the volume of a solid tumor of a cancer associated with elevated ASCT2 expression in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an NKA inhibitor.
  • the volume is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.
  • the volume is reduced by at least at least 25%.
  • the volume is reduced by at least 50%.
  • the present disclosure provides methods of modulating the concentration of one or more biomarkers of a cancer associated with elevated ASCT2 expression in a cell comprising contacting the cell with an NKA inhibitor. In some embodiments, modulating decreases the concentration of the one or more biomarkers.
  • the modulating decreases the concentration of the one or more biomarkers by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the modulating decreases the concentration of the one or more biomarkers by at least 25%.
  • the modulating decreases the concentration of the one or more biomarkers by at least 50%. In some embodiments, the modulating decreases the concentration of the one or more biomarkers modulating increases the concentration of the one or more biomarkers. In some embodiments, the modulating increases the concentration of the one or more biomarkers by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.
  • the one or more biomarkers are selected from: glutamine, glutamate, a-ketoglutarate (a-KG), 2-hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, lactate, and fumarate.
  • modulating decreases the concentration of the one or more biomarkers selected from: glutamine, glutamate, a-ketoglutarate (a-KG), 2- hydroxyglutarate (2HG), glutathione (GSH), malate, pyruvate, and lactate.
  • modulating increases the concentration of fumarate.
  • the level of NADH or NADPH is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the level of NADH or NADPH is reduced by at least 50%.
  • the present disclosure provides methods of suppressing ASCT2 protein expression in a cell comprising contacting the cell with an NKA inhibitor.
  • the present disclosure provides methods of reducing the rate of proliferation of a cancer cell comprising contacting the cell with an NKA inhibitor, wherein the cancer is associated with elevated ASCT2 expression.
  • the rate of proliferation is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.
  • the rate of proliferation is reduced by at least 10%.
  • the rate of proliferation is reduced by at least at least 30%.
  • the cellular concentration of the NKA inhibitor is from about 0.1 ng/mL to about 100 ng/mL, from about 1 ng/mL to about 50 ng/mL, or from about 0.1 ng/mL, 0.2 ng/mL, 0.3 ng/mL, 0.4 ng/mL, 0.5 ng/mL, 0.6 ng/mL, 0.7 ng/mL, 0.8 ng/mL, 0.9 ng/mL, 1 ng/mL, 2 ng/mL, 3 ng/mL, 4 ng/mL, 5 ng/mL, 6 ng/mL, 7 ng/mL, 8 ng/mL, 9 ng/mL, 10 ng/mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, 30 ng/mL, 35 ng/mL, 40 ng/mL, 45 ng/mL, 50 ng/mL,
  • the cellular concentration of the NKA inhibitor is about 3 ng/mL. In some embodiments, the cellular concentration of the NKA inhibitor is about 30 ng/mL.
  • the cancer is of the bile duct, bladder, brain, breast, cervix, colon, esophagus, kidney, liver, lung, lymph node, mouth, ovary, pancreas, prostate, rectum, skin, stomach, throat, thymus, thyroid, or uterus.
  • the cancer is bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC/HCC), lung adenocarcinoma (LU AD), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), rectum adenocarcinoma
  • the cancer is of the bile duct, brain, liver, mouth, or throat. In some embodiments, the cancer is of the bile duct. In some embodiments, the cancer is cholangiocarcinoma (CHOL). In some embodiments, the cancer is of the brain. In some embodiments, the cancer is glioblastoma multiforme (GBM). In some embodiments, the cancer is of the liver. In some embodiments, the cancer is liver hepatocellular carcinoma (LIHC/HCC). In some embodiments, the cancer is of the mouth or throat. In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSC).
  • HNSC head and neck squamous cell carcinoma
  • the NKA inhibitor is a bufadienolide derivative, or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound of formula (I): wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; and
  • Ri, R2, R3, R4, R5, Re, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or
  • R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
  • Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
  • R13 is selected from hydrogen, optionally substituted alkyl, and formyl
  • Li is selected from a covalent bond, *-C(0)0-, *-[C(R a )(Rb)]s-O-, and *-[C(R a )(Rb)]s- C(0)0-, wherein * indicates the point of attachment of Li to Z, further wherein: R a and Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • R a and Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; or
  • R15 and one occurrence of R3 are together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Z is selected from -OR14 and -NR15R16, wherein:
  • Ris is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ri6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20
  • R15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Wi is selected from the following moi eties: wherein: m is selected from 0, 1, 2, and 3;
  • Y is selected from O and NR24;
  • R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl;
  • R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound of formula (I): wherein: each dashed bond independently represents a single bond or a double bond; n, p, and q are independently selected from 0 and 1; and
  • Ri, R2, R3, R4, R5, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or
  • R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
  • Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
  • R13 is selected from hydrogen, optionally substituted alkyl, and formyl
  • Li is selected from a covalent bond, *-C(O)O-, *-[C(R a )(Rb)]s-O-, and *-[C(R a )(Rb)]s- C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein: R a and Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • R a and Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; or
  • R15 and one occurrence of Ra are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Z is selected from -ORu and -NR15R16, wherein:
  • R17 and Ris are independently selected from hydrogen and optionally substituted alkyl
  • R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ri6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR.2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R
  • R15 and Ri6 are taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Wi is selected from the following moi eties: wherein: m is selected from 0, 1, 2, and 3;
  • Y is selected from O and NR24;
  • R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl;
  • R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound of formula (I-A):
  • each dashed bond independently represents a single bond or a double bond
  • n, p, and q are independently selected from 0 and 1;
  • Ri, R2, R3, R4, R5, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or
  • R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
  • Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
  • R13 is selected from hydrogen, optionally substituted alkyl, and formyl
  • Li is selected from a covalent bond, *-C(O)O-, *-[C(R a )(Rb)]s-O-, and *-[C(R a )(Rb)]s- C(O)O-, wherein * indicates the point of attachment of Li to Z, further wherein: R a and Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
  • R a and Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; or
  • R15 and one occurrence of Ra are together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Z is selected from -ORu and -NR15R16, wherein:
  • R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ri6 is selected from hydrogen, hydroxyl, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, -COR19, -CO2R19, -CONR20R21, -C(NR22)NR2oR2i, -C(NCN)NR2oR2i, -SO2R19, and -SO2NR20R21, where R19 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R20, R21 and R22 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R20
  • Wi is selected from the following moi eties: wherein: m is selected from 0, 1, 2, and 3;
  • Y is selected from O and NR24;
  • R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl;
  • R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
  • Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
  • R13 is selected from hydrogen, optionally substituted alkyl, and formyl
  • R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Wi is selected from the following moi eties: wherein: m is selected from 0, 1, 2, and 3; wherein Y is selected from O and NR24;
  • R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl;
  • R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • the NKA inhibitor is a compound of Formula (II- A):
  • Ri, R2, R3, R4, Rs, Rs, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or
  • R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
  • Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
  • R13 is selected from hydrogen, optionally substituted alkyl, and formyl
  • R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ri6 is -CONR20R21, where R20 and R21 are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Wi is selected from the following moi eties: wherein: m is selected from 0, 1, 2, and 3;
  • Y is selected from O and NR24;
  • R23 is selected from cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl; and
  • R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound of formula (III):
  • n is selected from 0 and 1;
  • Ri, R2, R3, R5, Re, R9, Rio, R11 and R12 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino; or
  • R4 is hydroxy, or R4 and R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R7 is selected from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
  • Rs is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
  • RB is selected from hydrogen, optionally substituted alkyl, and formyl;
  • Z is selected from ORu and NR15R16; wherein:
  • R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ri6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R15 and Ri6 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • Wi is selected from the following moi eties: wherein: m is selected from 0, 1, 2, and 3;
  • Y is selected from O and NR24;
  • R24 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • W2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl; or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound of formula (III), or a pharmaceutically acceptable salt thereof, provided that when R4 is OH, R13 is methyl, Wi is
  • R12 is not hydrogen
  • the NKA inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents a single bond or a double bond; n is selected from 0 and 1;
  • Ri, R2, Rs, Rs, Rio, R11, R12 and W2 are hydrogen;
  • R3 and R9 are independently hydrogen or OH;
  • R4 is hydroxy and Rs is hydrogen, or R4 and Rs may optionally be joined together with any intervening atoms to form an oxirane ring;
  • R 7 is -OCOCH3
  • R13 is methyl
  • Z is NR15R16, wherein:
  • Ris is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;
  • Rie is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; or R15 and Rie are joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and
  • the NKA inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof, provided that the compound is not a compound of
  • R3, R5, Rs, R7, Rs, R9, Rio, R11, R12 and W2 are hydrogen.
  • the NKA inhibitor is:
  • Z is selected from OR14 and NR15R16, wherein:
  • R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Ri6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R15 and Ri6 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; (b) a compound of Formula (IV-B):
  • R15 and Ri6 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or Ri and R2 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R a and Rb are independently selected at each occurrence from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or Ra and Rb are taken together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; or R15 and one occurrence of Ra taken together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and s is selected from 1, 2, 3, 4, 5 and 6; or
  • R a is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • the NKA inhibitor is a compound of Formula (IV-A) or a pharmaceutically acceptable salt thereof.
  • Z is OR14.
  • R14 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.
  • Z is NR15R16.
  • R15 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl
  • Ri6 is selected from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.
  • the compound of Formula IV-A is selected from: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;
  • the NKA inhibitor is a compound of Formula (IV-B) or a pharmaceutically acceptable salt thereof. In some embodiments, the NKA inhibitor is a compound of Formula (IV-C) or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound selected from:
  • the NKA inhibitor is a compound selected from: l-(2-aminoethyl)-3-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2- oxo-2H-pyran-5-yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl)-3-(2 -hydroxy ethyl)urea; l-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo
  • the NKA inhibitor is a compound selected from:
  • the NKA inhibitor is a compound selected from:
  • the NKA inhibitor is a compound selected from: (lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;
  • the NKA inhibitor is a compound selected from: (lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl (2-(pyrrolidin- 1 -yl)ethyl) carbonate;
  • the NKA inhibitor is a compound selected from: (lR,2aR,3aS,3bR,5aR,7S,9aS,9bS,l laR)-9a,l la-dimethyl-l-(2-oxo-2H-pyran-5- yl)hexadecahydronaphtho[ l',2' : 6,7]indeno[ 1 ,7a-b]oxiren-7-yl 4-m ethylpiperazine- 1 - carboxylate;
  • the NKA inhibitor is a compound selected from: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl (2-(pyrrolidin-l-yl)ethyl) carbonate;
  • the NKA inhibitor is a compound selected from:
  • the NKA inhibitor is a compound selected from: (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5- yl)hexadecahydro-lH-cyclopenta[a]phenanthren-3-yl piperazine- 1 -carboxylate; or a pharmaceutically acceptable salt thereof.
  • the NKA inhibitor is a compound selected from digoxin and digitoxin, or a pharmaceutically acceptable salt thereof. In some embodiments, the NKA inhibitor is a compound disclosed in US 2013/0005696 or WO 2013/000286, or a pharmaceutically acceptable salt thereof.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH2 is attached through the carbon atom.
  • optionally substituted alkyl encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.
  • alkyl refers to straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms.
  • Ci-Ce alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refers to alkyl groups having one to six carbons.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, 3 -methylpentyl, and the like.
  • Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms.
  • Co alkylene indicates a covalent bond
  • Ci alkylene is a methylene group.
  • alkenyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the parent alkyl.
  • the group may be in either the cis or trans configuration about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en- 2-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but- 2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl; and the like.
  • an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms. “Lower alkenyl” refers to alkenyl groups having two to six carbons.
  • alkynyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl; and the like.
  • an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms.
  • “Lower alkynyl” refers to alkynyl groups having two to six carbons.
  • cycloalkyl refers to a non-aromatic carbocyclic ring, usually having from 3 to 8 ring carbon atoms. The ring may be saturated or have one or more carboncarbon double bonds.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groups such as norbornane.
  • alkoxy refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3 -methylpentyloxy, and the like. Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refers to alkoxy groups having one to six carbons.
  • acyl refers to the groups H-C(O)-; (alkyl)-C(O)-; (cycloalkyl)- C(O)-; (aryl)-C(O)-; (heteroaryl)-C(O)-; and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein.
  • Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms.
  • acyloxy refers to the group -O-acyl.
  • a Ci-Ce alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • alkoxycarbonyloxy refers to the group -O-alkoxy carbonyl.
  • amino refers to the group -NH2.
  • mono- and di-(alkyl)amino refers to secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
  • aminocarbonyl refers to the group -C(O)NR b R c , where:
  • R b is selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, optionally substituted alkoxy; and
  • R c is selected from hydrogen and optionally substituted C1-C4 alkyl
  • R b and R c taken together with the nitrogen to which they are bound, form an optionally substituted 5- to 8-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NEE, -N(CI-C4 alkyl)(Ci-C4 alkyl), -NH(Ci-C
  • aminocarbonyloxy refers to the group -O-aminocarbonyl.
  • aryl refers to: 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • aryl includes 6-membered carbocyclic aromatic rings fused to a 5- to 7- membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O, and S.
  • bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • aryloxy refers to the group -O-aryl.
  • aralkyl refers to the group -alkyl-aryl.
  • R e is selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R f and R s are independently selected from hydrogen optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided that at least one of R e , R f , and R s is not hydrogen and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from
  • R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is selected from hydrogen and optionally substituted C1-C4 alkyl
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH 2 , -N(CI-C 4 alkyl)(Ci-C 4 alkyl), -NH(CI-C 4 alkyl), -N(CI-C 4 alkyl)(C
  • halo refers to fluoro, chloro, bromo, and iodo
  • halogen includes fluorine, chlorine, bromine, and iodine
  • haloalkyl refers to alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, di fluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • heteroaryl refers to:
  • heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring.
  • bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at either ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3 -pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4- pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein.
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O') substituents, such as pyridinyl N-oxides.
  • heteroaryloxy refers to the group -O-heteroaryl.
  • heteroaryl refers to the group -alkyl-heteroaryl.
  • heterocycloalkyl refers to a single, non-aromatic ring, usually with
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2- piperidyl, 3-piperidyl, 4-piperidyl, 4-piperazinyl, and 2,5-piperizinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 8 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 8 ring atoms, optionally contains 1-3 heteratoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • heterocycloalkloxy refers to the group -O-heterocycloalkyl.
  • sulfanyl refers to the groups: -S-(optionally substituted (Ci-
  • sulfanyl includes the group Ci-Ce alkyl sulfanyl.
  • sulfinyl refers to the groups: -S(O)-(optionally substituted (Ci- Ce)alkyl), -S(O)-optionally substituted aryl), -S(O)-optionally substituted heteroaryl), -S(O)- (optionally substituted heterocycloalkyl); and -S(O)-(optionally substituted amino).
  • sulfonyl refers to the groups: -S(O)2-(optionally substituted (Ci- Ce)alkyl), -S(O)2-optionally substituted aryl), -S(O)2-optionally substituted heteroaryl), -S(O)2- (optionally substituted heterocycloalkyl), and -S(O)2-(optionally substituted amino).
  • aminosulfonyl refers to the group -S(O)2NR b R c , where:
  • R b is selected from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, optionally substituted alkoxy; and
  • R c is selected from hydrogen and optionally substituted C1-C4 alkyl
  • R b and R c taken together with the nitrogen to which they are bound, form an optionally substituted 5- to 8-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(CI-C4 alkyl)(Ci-C4 alkyl), -NH(Ci-C4
  • substituted refers to any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded.
  • 2 hydrogens on the atom are replaced.
  • substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from
  • R a is selected from optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is selected from hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is selected from hydrogen and optionally substituted C1-C4 alkyl

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Abstract

La présente divulgation concerne des méthodes de traitement ou de prévention d'un cancer associé à une expression élevée de l'ASCT2 chez un patient dont l'état le nécessite, consistant en l'administration au patient d'une quantité thérapeutiquement efficace d'un inhibiteur de la Na+/K+-ATPase (NKA). La divulgation concerne également des méthodes supplémentaires utilisant des inhibiteurs de la Na+/K+-ATPase (NKA).
EP23892424.5A 2022-11-16 2023-11-14 Traitement de cancers dépendants de l'asct2 Pending EP4619106A2 (fr)

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US202263384062P 2022-11-16 2022-11-16
PCT/US2023/079681 WO2024107753A2 (fr) 2022-11-16 2023-11-14 Traitement de cancers dépendants de l'asct2

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090186837A1 (en) * 2002-12-27 2009-07-23 The Trustees Of Columbia University In The City Of New York Anti-neoplastic compositions comprising extracts of black cohosh
US20060135468A1 (en) * 2004-09-02 2006-06-22 Bionaut Pharmaceuticals, Inc. Treatment of refractory cancers using NA+/K+ ATPase inhibitors
EP3897657A2 (fr) * 2018-12-20 2021-10-27 Universität Basel Inhibiteurs de na + k + atpase destinés à être utilisés dans la prévention ou le traitement de métastases

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