WO2024107996A1 - Metap2 inhibitors for the treatment of prostate cancer - Google Patents

Metap2 inhibitors for the treatment of prostate cancer Download PDF

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Publication number
WO2024107996A1
WO2024107996A1 PCT/US2023/080080 US2023080080W WO2024107996A1 WO 2024107996 A1 WO2024107996 A1 WO 2024107996A1 US 2023080080 W US2023080080 W US 2023080080W WO 2024107996 A1 WO2024107996 A1 WO 2024107996A1
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Prior art keywords
prostate cancer
enzalutamide
subject
metap2 inhibitor
treatment
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PCT/US2023/080080
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French (fr)
Inventor
James Shanahan
Bradley J. CARVER
Benjamin MAYES
Peter Cornelius
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Syndevrx, Inc.
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Publication date
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Publication of WO2024107996A1 publication Critical patent/WO2024107996A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Prostate cancer is the second-most diagnosed malignancy and is the leading cause of cancer death worldwide among men. More specifically, treatment of advanced prostate cancer with androgen deprivation therapy and androgen receptor antagonists (e.g. enzalutamide) has only provided incremental improvements in survival, as patients inevitably develop resistance. Moreover, continuous androgen deprivation or receptor inhibition therapy has been shown to drive systemic metabolic dysfunction, including weight gain, increased insulin resistance, hyperleptinaemia and reduced circulating adiponectin. Such dysfunctions have been shown to lead to molecular reprogramming in tumours that may be in at least in part responsible for the development of treatment resistance. Finally, elevated expression of the enzyme methionine aminopeptidase type 2 (MetAP2) has recently been shown to be associated with higher grade tumours, including neuroendocrine tumours, and worse clinical outcomes.
  • MetAP2 methionine aminopeptidase type 2
  • AR androgen receptor pathway inhibitors for the treatment of metastatic castrateresistant prostate cancer
  • mCRPC metastatic castrateresistant prostate cancer
  • AR inhibition causes major molecular reprograming in tumors, which has resulted in the emergence of highly aggressive and difficult-to-treat molecular subtypes of prostate cancer, termed aggressive variant prostate cancer (AVPC).
  • AVPC is a general term for tumors representing the transition from an adenocarcinoma phenotype, toward less differentiated anaplastic phenotypes, which are driven by alternate non-AR mechanisms to promote tumor growth and survival.
  • compositions and methods directed to the treatment of prostate cancer including treatments that target MetAP2 and/or that mitigate treatment- induced metabolic dysfunctions.
  • the present disclosure provides MetAP2 inhibitors and combinations comprising MetAP2 inhibitors for the treatment of prostate cancer.
  • the present disclosure provides methods of treating prostate cancer in a subject, the methods comprising administering at least one amount of at least one MetAP2 inhibitor to the subject, wherein the MetAP2 inhibitor is: salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30: 1 to about 3: 1, preferably wherein the ratio of x to y is about 11 : 1, wherein the subject has been previously administered at least one prostate cancer treatment, wherein the prostate cancer treatment comprises androgen deprivation therapy (ADT) and/or at least one androgen receptor antagonist, wherein the prostate cancer has become resistant to treatment with the androgen deprivation therapy (ADT) and/or at least one androgen receptor antagonist, wherein administration of the MetAP2 inhibitor results in reduction in size of the prostate cancer.
  • the MetAP2 inhibitor is: salt thereof, wherein x is in the range of 1
  • the methods further comprise administering to the subject at least one amount of enzalutamide.
  • the prostate cancer is castration-resistant prostate cancer.
  • the prostate cancer is castration-sensitive prostate cancer.
  • the prostate cancer is androgen receptor-inhibition resistant prostate cancer.
  • the prostate cancer is castration-resistant and androgen receptor inhibition-resistant prostate cancer.
  • the prostate cancer is PTEN-deficient prostate cancer or partially PTEN-deficient prostate cancer.
  • the prostate cancer is PTEN-altered prostate cancer or partially PTEN- altered prostate cancer.
  • the prostate cancer is aggressive variant prostate cancer (AVPC).
  • AVPC aggressive variant prostate cancer
  • the prostate cancer is neuroendocrine prostate cancer (NEPC).
  • NEPC neuroendocrine prostate cancer
  • the androgen deprivation therapy comprises performing an orchiectomy, administering at least one luteinizing hormone-releasing hormone (LHRH) agonist, administering at least one LHRH antagonist, administering at least one estrogen, or any combination thereof.
  • the orchiectomy is a subcapsular orchiectomy.
  • the at least one LHRH agonist is selected from leuprolide, goserelin, triptorelin and histrelin.
  • the at least one LHRH antagonist is selected from degarelix and relugolix.
  • the at least one androgen receptor antagonist is selected from flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide, preferably wherein the at least one androgen receptor antagonist is enzalutamide.
  • the MetAP2 inhibitor is administered within one day, two days, three days, four days, five days, six days, one week or two weeks of the subject exhibiting PSA nadir. [0018] In some aspects, the MetAP2 inhibitor is administered about two weeks, or about three weeks, or about four weeks, about five weeks, or about six weeks, or about seven weeks, or about eight weeks after the subject has exhibited PSA nadir, and wherein the PSA level in the subject has increased from PSA nadir.
  • the subject has at least one metabolic dysfunction, wherein the metabolic dysfunction is selected from visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated HbAlc, or any combination thereof.
  • the metabolic dysfunction is a prostate cancer treatment-induced metabolic dysfunction.
  • the MetAP2 inhibitor is administered to the subject in an amount of: i) about 27 mg/m 2 ; ii) about 36 mg/m 2 ; iii) about 49 mg/m 2 ; or iv) about 65 mg/m 2 .
  • MetAP2 inhibitor is administered: i) once every 7 days (Q7D); ii) once every 14 days (Q14D); or iii) once every 21 days (Q21D).
  • the enzalutamide is administered to the subject in an amount of: i) about 40 mg; ii) about 80 mg; iii) about 120 mg; or iv) about 160 mg.
  • the enzalutamide is administered daily. In some aspects, the enzalutamide is administered weekly.
  • FIG. 1 shows the tumor volume in individual mice (left panel) and the average tumor volume across all mice (right panel) in experimental treatment groups described in Example 1.
  • FIG. 2 shows the average PSA levels of mice (left panel) and the endpoint tumor mass (right panel) in experimental treatment groups described in Example 1.
  • FIG. 3 shows the body weight of individual mice (left panel) and the average body weight across all mice (right panel) in experimental treatment groups described in Example 1.
  • FIG. 4 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 1.
  • FIG. 5 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 1.
  • FIG. 6 is a graph showing the overall survival of the mice in experimental treatment groups described in Example 1.
  • FIG. 7 shows necropsy images of tumors excised from mice in the experimental treatment groups described in Example 1.
  • FIG. 8 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 1.
  • FIG. 9 shows the average tumor volume across all mice in the experimental treatment groups described in Example 2.
  • FIG. 10 shows the tumor mass at the conclusion of the study in the experimental treatment groups described in Example 2.
  • FIG. 11 shows the average PSA levels across all mice during the course of the study in the experimental treatment groups described in Example 2.
  • FIG. 12 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 2.
  • FIG. 13 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 2.
  • FIG. 14 shows the average body weight across all mice in experimental treatment groups described in Example 2.
  • FIG. 15 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 2.
  • FIG. 16 shows the tumor volume in individual mice (top panel) and the average tumor volume across all mice (bottom panel) in the experimental treatment groups described in Example 3.
  • FIG. 17 shows the endpoint tumor mass (left panel) and average PSA levels of mice (right panel) in the experimental treatment groups described in Example 3.
  • FIG. 18 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the experimental treatment groups described in Example 3.
  • FIG. 19 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 3.
  • FIG. 20 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 3.
  • FIG. 21 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 3.
  • FIG. 22 the average tumor volume in the experimental treatment groups described in Example 4.
  • FIG. 23 the average tumor volume in the experimental treatment groups described in Example 4.
  • FIG. 24 shows the endpoint tumor mass in the experimental treatment groups described in Example 4.
  • FIG. 25 shows the average PSA levels of mice in the experimental treatment groups described in Example 4.
  • FIG. 26 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the experimental treatment groups described in Example 4.
  • FIG. 27 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 4.
  • FIG. 28 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 4.
  • FIG. 29 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 4.
  • FIG. 30 shows the average tumor volume in the experimental treatment groups described in Example 5.
  • FIG. 31 shows the endpoint tumor mass in the experimental treatment groups described in Example 5.
  • FIG. 32 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 5.
  • FIG. 33 A is a graph showing average tumor volume across all mice in the two treatment groups described in Example 7.
  • FIG. 33B is a graph showing endpoint tumor volume in mice in the two treatment groups described in Example 7.
  • FIG. 33C shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 7.
  • FIG. 34A is a graph showing tumor volume of all mice in the two treatment groups described in Example 8.
  • FIG. 34B is a graph showing average tumor volume across all mice in the two treatment groups described in Example 8.
  • FIG. 34C is a graph showing tumor weight reduction across all mice in the two treatment groups described in Example 8.
  • FIG. 35 shows a chart of the number of differentially expressed human genes for each pairwise comparison of treatment groups described in Examples 1-5 (left panel) and bubble plots of a selection of significantly enriched (adj. p value ⁇ 0.05) cellular pathways from the MSigDB (Molecular Signatures Database) for each of the comparisons (right panel).
  • MSigDB Molecular Signatures Database
  • FIGs. 36, 37, 38, 39 and 40 show bubble plots of genes of interest including for pairwise comparisons of treatment groups described in Examples 1-5.
  • FIG. 41 shows the expression levels of particular hypoxia induced, extracellular matrix-related genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIGs. 42A and 42B show the expression levels of particular glycolysis-related genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 43 shows the expression levels of particular serine-glycine one-carbon (SOGC) pathway genes in tumor samples from the experimental treatment groups described in Example 5.
  • SOGC serine-glycine one-carbon
  • FIG. 44 shows the expression levels of particular cholesterol uptake and synthesis pathway genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 45 shows the expression levels of particular fatty acid synthesis pathway genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 46 shows the expression levels of particular cell cycle genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 47 shows the expression levels of particular hormone/cytokine receptor genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 48 shows the expression levels of particular kinase genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 49 shows the expression levels of particular transcription factor genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 50 shows the expression levels of particular tumor-inhibiting genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIGs. 51 A and 5 IB show the expression levels of particular tumor-growth promoting/survival genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 52 shows the expression levels of particular nucleotide synthesis genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 53 shows the expression levels of particular lipid metabolism genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 54 shows the expression levels of particular immune recognition genes in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 55 shows the expression levels of particular immune recognition genes, specifically CD74 ligands and binding partners, in tumor samples from the experimental treatment groups described in Example 5.
  • FIG. 56 shows the expression levels of particular genes encoding regulators of MHC II, in tumor samples from the experimental treatment groups described in Example 5. DETAILED DESCRIPTION
  • the present disclosure provides, inter alia, a method of treating prostate cancer comprising administering to a subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, or comprising administering to a subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent.
  • the present disclosure provides methods of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject in need thereof.
  • the present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prostate cancer in a subject in need thereof.
  • the present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer in a subject in need thereof.
  • the present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of prostate cancer in a subject in need thereof.
  • the present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence in a subject in need thereof.
  • the present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of prostate cancer growth or recurrence in a subject in need thereof.
  • the present disclosure provides a combination therapy comprising at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding combination therapy.
  • the present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding combination therapy.
  • the present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding combination therapy.
  • the present disclosure provides a pharmaceutical composition comprising at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding pharmaceutical compositions.
  • the present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding pharmaceutical compositions.
  • the present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding pharmaceutical compositions.
  • the present disclosure provides a kit comprising at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding kit.
  • the present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding kit.
  • the present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding kit.
  • the present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer.
  • the present disclosure provides a use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer.
  • the present disclosure provides a use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer growth or recurrence.
  • the present disclosure provides a use of enzalutamide, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer.
  • the present disclosure provides a use of enzalutamide, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer.
  • the present disclosure provides a use of enzalutamide, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer growth or recurrence.
  • the present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of prostate cancer.
  • the present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention of prostate cancer.
  • the present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention of prostate cancer growth or recurrence.
  • the present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in treating prostate cancer.
  • the present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer.
  • the present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer growth or recurrence.
  • the present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in treating prostate cancer.
  • the present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer.
  • the present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer growth or recurrence.
  • the present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer.
  • the present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer.
  • the present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence.
  • the present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer, wherein the combination further comprises enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination comprising enzalutamide, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer, wherein the combination further comprises enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence, wherein the combination further comprises enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination comprising enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination comprising enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof [00135]
  • the present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer, wherein the method further comprises administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer, wherein the method further comprises administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence, wherein the method further comprises administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof can be administered by the same administration route.
  • a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof can be administered by different administration routes.
  • a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof can be administered concurrently.
  • a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof can be administered in temporal proximity.
  • a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof can be administered in any order.
  • the administration of a MetAP2 inhibitor and/or the administration of a MetAP2 inhibitor in combination with enzalutamide results in a decrease in angiogenesis in at least one tumor in the subject.
  • the decrease is at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, at least a 95%, or at least a 99% decrease in angiogenesis.
  • the administration of a MetAP2 inhibitor and/or the administration of a MetAP2 inhibitor in combination with enzalutamide results in a decrease in the expression level of at least one gene selected from P4HA1, LOX, GLUT1/SLC2A1, HK2, PDK1FKFB3, FKFB4, PKM, ENO1, LDHA, GLS, PHGDH, SHMT2, TYMS, PSPH, LDL receptor, SQLE, HMGCR, ACACA, ACLY, SCD, CCNB1, CXCR4, FZD8, FZD3, IGFlr, MAP2K6, MAPK13, AURKA, AURKB, EZH2, F0XM1, MYB, SREBF1, MYBL2, BIRC5, ANTRX1, DPYLS3, HMMR, BAG1, Ki67, CCNB1, PCLAF, TK1, RRM2, TK1, RRM1, RRM2, PLA2G2A, M
  • the decrease is at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, at least a 95%, or at least a 99% decrease in expression.
  • the administration of a MetAP2 inhibitor and/or the administration of a MetAP2 inhibitor in combination with enzalutamide results in an increase in the expression level of at least one gene selected from CDKN2B, PIK3IP1, SH3BGRL2, CD 177, HLA-DRA, HLA-E, HLA-DMA, HLA-DMB, CD74, CIITA, IFI30.
  • the increase is at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, at least a 95%, or at least a 99% increase in expression.
  • MetAP2 inhibitors described herein can be used in the kits, pharmaceutical compositions, uses and methods described herein.
  • a MetAP2 inhibitor can be Compound 1, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 1 is represented by:
  • y is in the range of 1 to about 30 and n is in the range of 1 to about 100.
  • n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50.
  • the ratio of x to y can be in the range of about 30: 1 to about 3: 1.
  • a MetAP2 inhibitor can be Compound 2, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 2 is represented by:
  • n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50.
  • the ratio of x to y can be in the range of about 30:1 to about 3: 1.
  • a MetAP2 inhibitor can be Compound 3, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 3 is represented
  • n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50.
  • the ratio of x to y can be in the range of about 30:1 to about 3: 1.
  • a MetAP2 inhibitor can be Compound 4, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 4 is represented by:
  • Compound 4 wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100. In some aspects, n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50. In some aspects, the ratio of x to y can be in the range of about 30:1 to about 3: 1.
  • the MetAP2 inhibitor can be: derivative, salt or ester thereof.
  • the MetAP2 inhibitor can be: pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.
  • the MetAP2 inhibitor can be: salt, analog, derivative, salt or ester thereof.
  • the MetAP2 inhibitor can be:
  • the MetAP2 inhibitor can be: pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.
  • the MetAP2 inhibitor can be selected from cis-(3aRS,9bRS)-7-
  • a MetAP2 inhibitor can be selected from:
  • a MetAP2 inhibitor can be: pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.
  • a MetAP2 inhibitor can be administered by subcutaneous injection (SC). In some aspects, a MetAP2 inhibitor can be administered by subcutaneous injection to the mid-abdominal (per-umbilical area). In some aspects, a subcutaneous injection of a MetAP2 inhibitor can be administered over an about 30 to about 45 second timeframe at a constant injection rate. In some aspects, the maximum injection volume of a MetAP2 inhibitor is less than about 1.7 ml.
  • a MetAP2 inhibitor can be administered about every four days (Q4D).
  • a MetAP2 inhibitor can be administered about once every day (QD), about once every two days (Q2D), about once every three days (Q3D), about once every four days (Q4D), about once every 5 days (Q5D), about once every 6 days (Q6D), about once every 7 days (Q7D), about once every 8 days (Q8D), about once every 9 days (Q9D), about once every 10 days (Q10D), about once every 11 days (QI ID), about once every 12 days (QI 2D), about once every 13 days (QI 3D), about once every 14 days (Q14D), or about once every 15 days (Q15D).
  • a MetAP2 inhibitor can be administered about once every 7 days (Q7D).
  • a MetAP2 inhibitor can be administered about once every 14 days (Q14D).
  • an amount of a MetAP2 inhibitor can be a therapeutically effective amount of a MetAP2 inhibitor.
  • a MetAP2 inhibitor can be administered in an amount of about 1 mg/m 2 , or about 2 mg/m 2 , or about 3 mg/m 2 , or about 4 mg/m 2 , or about 5 mg/m 2 , or about 6 mg/m 2 , or about 7 mg/m 2 , or about 8 mg/m 2 , or about 9 mg/m 2 , or about 10 mg/m 2 , or about 11 mg/m 2 , or about 12 mg/m 2 , or about 13 mg/m 2 , or about 14 mg/m 2 , or about 15 mg/m 2 , or about 16 mg/m 2 , or about 17 mg/m 2 , or about 18 mg/m 2 , or about 19 mg/m 2 , or about 20 mg/m 2 , or about 21 mg/m 2 , or about 22 mg/m 2 , or about 23 mg/m 2 , or about 24 mg/m 2 , or about 25 mg/m 2 , or about 26 mg/m 2 , or
  • a MetAP2 inhibitor can be administered in an amount of about 49 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 36 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 65 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 27 mg/m 2 .
  • a MetAP2 inhibitor can be administered in an amount of about 49 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 39 mg/m 2 to about 59 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 44 mg/m 2 to about 54 mg/m 2 .
  • a MetAP2 inhibitor can be administered in an amount of about 36 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 26 mg/m 2 to about 49 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 31 mg/m 2 to about 65 mg/m 2 .
  • a MetAP2 inhibitor can be administered in an amount of about 65 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 55 mg/m 2 to about 75 mg/m 2 . In some aspects, a MetAP2 inhibitor can be administered in an amount of about 60 mg/m 2 to about 70 mg/m 2 .
  • a therapeutically effective amount of a MetAP2 inhibitor can be about 1 mg/m 2 , or about 2 mg/m 2 , or about 3 mg/m 2 , or about 4 mg/m 2 , or about 5 mg/m 2 , or about 6 mg/m 2 , or about 7 mg/m 2 , or about 8 mg/m 2 , or about 9 mg/m 2 , or about 10 mg/m 2 , or about 11 mg/m 2 , or about 12 mg/m 2 , or about 13 mg/m 2 , or about 14 mg/m 2 , or about 15 mg/m 2 , or about 16 mg/m 2 , or about 17 mg/m 2 , or about 18 mg/m 2 , or about 19 mg/m 2 , or about 20 mg/m 2 , or about 21 mg/m 2 , or about 22 mg/m 2 , or about 23 mg/m 2 , or about 24 mg/m 2 , or about 25 mg/m 2 , or about 26 mg/m 2 , or about 20 mg/m
  • a therapeutically effective amount of a MetAP2 inhibitor can be about 49 mg/m 2 . In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 39 mg/m 2 to about 59 mg/m 2 . In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 44 mg/m 2 to about 54 mg/m 2 .
  • a therapeutically effective amount of a MetAP2 inhibitor can be about 36 mg/m 2 . In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 26 mg/m 2 to about 49 mg/m 2 . In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 31 mg/m 2 to about 49 mg/m 2 .
  • a therapeutically effective amount of a MetAP2 inhibitor can be about 65 mg/m 2 . In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 55 mg/m 2 to about 75 mg/m 2 . In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 60 mg/m 2 to about 70 mg/m 2 .
  • a MetAP2 inhibitor can be administered in an amount of about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg or about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or about 200 mg.
  • a MetAP2 inhibitor can be administered in an amount of about 80 mg.
  • a MetAP2 inhibitor can be administered in an amount of about of about 70 mg to about 90 mg.
  • a MetAP2 inhibitor can be administered in an amount of about 75 mg to about 85 mg.
  • a therapeutically effective amount of a MetAP2 inhibitor can be about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg.
  • a therapeutically effective amount of a MetAP2 inhibitor can be about 80 mg.
  • a therapeutically effective amount of a MetAP2 inhibitor can be about of about 70 mg to about 90 mg.
  • a therapeutically effective amount of a MetAP2 inhibitor can be about 75 mg to about 85 mg.
  • enzalutamide has the following chemical structure:
  • enzalutamide may be identified by any of the following names: 4-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5- dimethyl-4-oxo-2-thioxo-l-imidazolidinyl]-2-fluoro-7V-methylbenzamide, MDV 3100, Xtandi, and S -Enzalutamide.
  • enzalutamide may be identified as CAS No. 915087-33-1. In the figures accompanying the present disclosure, enzalutamide may be abbreviated “ENZ” or “Enz”.
  • enzalutamide can be administered orally.
  • an amount of enzalutamide can be a therapeutically effective amount of enzalutamide.
  • an amount of enzalutamide can be any of the amounts listed below.
  • enzalutamide can be administered in an amount of about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg, or about 180 mg, or about 200 mg, or about 220 mg, or about 240 mg, or about 260 mg, or about 280 mg, or about 300 mg, or about 320 mg, or about 340 mg, or about 360 mg, or about 380 mg, or about 400 mg, or about 420 mg, or about 440 mg, or about 460 mg, or about 480 mg, or about 500 mg.
  • enzalutamide can be administered in an amount of about 160 mg. In aspects wherein enzalutamide is administered in an amount of about 160 mg, the amount can be administered by orally administering four capsules of 160 mg.
  • a therapeutically effective amount of enzalutamide can be any of the enzalutamide amounts described herein.
  • enzalutamide can be administered as a pharmaceutical composition, wherein the pharmaceutical composition comprises capryl ocaproyl polyoxylglycerides.
  • the pharmaceutical composition can comprise at least one of caprylocaproyl polyoxylglycerides, butylated hydroxy anisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide [00187]
  • enzalutamide can be administered about once a day.
  • cancer and ’’cancerous refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • the prostate cancer can be androgen receptor-positive (AR+) prostate cancer.
  • AR+ androgen receptor-positive
  • the prostate cancer is androgen sensitive prostate cancer.
  • the prostate cancer is a prostate cancer that has reverted to an androgen sensitive state from an androgen-insensitive state.
  • the prostate cancer can be castration-resistant prostate cancer.
  • the prostate cancer is castration-sensitive prostate cancer.
  • the prostate cancer is metastatic.
  • the prostate cancer can be phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-deficient prostate cancer. In some aspects, the prostate cancer can be partially PTEN-deficient prostate cancer.
  • PTEN tensin homologue deleted on chromosome 10
  • the prostate cancer can be PTEN-altered prostate cancer. In some aspects, the prostate cancer can be partially PTEN-altered prostate cancer.
  • the prostate cancer is metastatic prostate cancer. [00198] In some aspects, the prostate cancer is advanced prostate cancer.
  • the prostate cancer is aggressive variant prostate cancer (AVPC).
  • the prostate cancer is neuroendocrine prostate cancer (NEPC).
  • the prostate cancer is resistant to treatment using androgen deprivation therapy (ADT).
  • ADT can include, but is not limited to, performing an orchiectomy, administering at least one luteinizing hormone-releasing hormone (LHRH) agonist, administering at least one LHRH antagonist, administering at least one estrogen, or any combination thereof.
  • LHRH luteinizing hormone-releasing hormone
  • an orchiectomy can comprise the removal or one or two testicles from a subject.
  • an orchiectomy can be a subcapsular orchiectomy, wherein only the tissues in the testicles that produce androgen are removed, rather than the entire testicle.
  • LHRH agonists include, but are not limited to, leuprolide, goserelin, triptorelin and histrelin.
  • LHRH antagonists include, but are not limited to, degarelix and relugolix.
  • the prostate cancer is resistant to treatment using an androgen receptor antagonist or inhibitor.
  • the prostate cancer has progressed while the subject has been on a treatment regimen comprising the administration of at least one androgen receptor antagonist or inhibitor.
  • androgen receptor antagonists or inhibitors include, but are not limited to flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide.
  • the prostate cancer is resistant to treatment using enzalutamide.
  • the prostate cancer has progressed while the subject has been on a treatment regimen comprising the administration of enzalutamide.
  • the prostate cancer can be PTEN-deficient, castration resistant prostate cancer.
  • the subject in need thereof is an animal.
  • the animal can be a mammal.
  • the subject in need thereof is a human.
  • the subject in need thereof is a human of 18 years or older, or of 25 years or older, or of 50 years or older, or of 60 years or older, or of 65 years or older, or of 70 years or older, or of 75 years or older, or of 80 years or older, or of 85 years or older.
  • the subject has been previously administered at least one androgen deprivation therapy (ADT).
  • ADT androgen deprivation therapy
  • the subject has been previously administered at least one androgen receptor antagonist and at least one androgen deprivation therapy.
  • a subject in need thereof has at least one metabolic dysfunction.
  • the at least one metabolic dysfunction can be excessive visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated HbAlc, or any combination thereof.
  • the at least one metabolic dysfunction is a treatment-induced metabolic dysfunction.
  • the metabolic dysfunction is a treatment- induced metabolic dysfunction that is induced by the treatment with at least one androgen deprivation therapy and/or at least one androgen receptor antagonist.
  • Certain compounds of the present disclosure may exist in particular geometric or stereoisomeric forms.
  • the present disclosure contemplates all such compounds, including cis- and trans-i somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure. Any representation of a particular isomer is merely exemplary (e.g., the exemplification of a trans-isomer, also encompasses a cis-isomer).
  • a particular enantiomer of a compound of the present disclosure may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomer.
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.
  • a crystal polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present disclosure. Furthermore, so-called metabolite which is produced by degradation of the present compound in vivo is included in the scope of the present disclosure.
  • “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture”.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques; it has been possible to separate mixtures of two atropic isomers in select cases.
  • Tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
  • Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide- imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine.
  • the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include monohydrates, dihydrates, etc.
  • solvates include ethanol solvates, acetone solvates, etc.
  • Solvate means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative refers to compounds that have a common core structure, and are substituted with various groups as described herein.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, (Rem. Rev. 96, 3147-3176, 1996.
  • Temporal proximity may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered.
  • Clinical benefit can be measured by assessing various endpoints, e.g., inhibition, to some extent, of disease progression, including slowing down and/or complete arrest; reduction in the number of disease episodes and/or symptoms; reduction in lesion size; inhibition (i.e., reduction, slowing down or complete stopping) of disease cell infiltration into adjacent peripheral organs and/or tissues; inhibition (i.e.
  • autoimmune response which may, but does not have to, result in the regression or ablation of the disease lesion
  • relief, to some extent, of one or more symptoms associated with the disorder increase in the length of disease-free presentation following treatment, e.g., progression-free survival; increased overall survival; higher response rate; decreased mortality at a given point of time following treatment; and/or improvement in one of the following symptoms: congestion, fluid/edema, wheezing, coughing, hypoxemia, low oxygen saturation, lung stiffness, shortness of breath, shortness of breath during exercise, dry hacking cough, fast shallow breathing, weight loss, tiredness, aching joints, aching muscles and clubbing.
  • the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “combination therapy” or “co-therapy” includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
  • any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models.
  • the term “subject” is interchangeable with the term “subject in need thereof’, both of which refer to a subject having a disease or having an increased risk of developing the disease.
  • a “subject” includes a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the mammal is a human.
  • the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • preventing describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • Embodiment la A method of treating prostate cancer in a subject, the method comprising administering at least one amount of at least one MetAP2 inhibitor to the subject.
  • Embodiment lb A method of preventing prostate cancer in a subject, the method comprising administering at least one amount of at least one MetAP2 inhibitor to the subject.
  • Embodiment 1c A method of preventing prostate cancer growth or recurrence in a subject, the method comprising administering at least one amount of at least one MetAP2 inhibitor to the subject.
  • Embodiment 2a A MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject.
  • Embodiment 2b A MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, for use in preventing prostate cancer in a subject.
  • Embodiment 2c A MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence in a subject.
  • Embodiment 3a A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject.
  • Embodiment 3b A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer in a subject.
  • Embodiment 3c A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence in a subject.
  • Embodiment 4a A method of treating prostate cancer in a subject, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • Embodiment 4b A method of preventing prostate cancer in a subject, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • Embodiment 4c A method of preventing prostate cancer growth or recurrence in a subject, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • Embodiment 5a A MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • Embodiment 5b A MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer in a subject, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • Embodiment 5c A MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence in a subject, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
  • Embodiment 6a Enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method further comprises administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.
  • Embodiment 6b Enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer in a subject, wherein the method further comprises administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.
  • Embodiment 6c Enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence in a subject, wherein the method further comprises administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.
  • Embodiment 7 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is castration-resistant prostate cancer.
  • Embodiment 8 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is castration-sensitive prostate cancer.
  • Embodiment 9a The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is PTEN-deficient prostate cancer or partially PTEN-deficient prostate cancer.
  • Embodiment 9b The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is PTEN-altered prostate cancer or partially PTEN-altered prostate cancer.
  • Embodiment 10 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is aggressive variant prostate cancer (AVPC).
  • AVPC aggressive variant prostate cancer
  • Embodiment 11 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).
  • NEPC neuroendocrine prostate cancer
  • Embodiment 12 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the at least one MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and the enzalutamide, or pharmaceutically acceptable salt thereof, are administered concurrently or in temporal proximity.
  • Embodiment 13 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one androgen deprivation therapy.
  • Embodiment 14 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has undergone an orchiectomy.
  • Embodiment 15 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 14, wherein the orchiectomy is a subcapsular orchiectomy.
  • Embodiment 16 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one luteinizing hormone-releasing hormone (LHRH) agonist.
  • LHRH luteinizing hormone-releasing hormone
  • Embodiment 17 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 16, wherein the at least one luteinizing hormone-releasing hormone (LHRH) agonist is selected from leuprolide, goserelin, triptorelin and histrelin.
  • LHRH luteinizing hormone-releasing hormone
  • Embodiment 18 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one LHRH antagonist.
  • Embodiment 19 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 18, wherein the at least one LHRH antagonist is selected from degarelix and relugolix.
  • Embodiment 20 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one androgen receptor antagonist.
  • Embodiment 21 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 20, wherein the androgen receptor antagonist is selected from flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide.
  • Embodiment 22 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 21, wherein the androgen receptor antagonist is enzalutamide.
  • Embodiment 23 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is resistant to treatment with androgen deprivation therapy.
  • Embodiment 24 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 23, wherein the androgen deprivation therapy comprises performing an orchiectomy, administering at least one luteinizing hormone-releasing hormone (LHRH) agonist, administering at least one LHRH antagonist, administering at least one estrogen, or any combination thereof.
  • LHRH luteinizing hormone-releasing hormone
  • Embodiment 25 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 24, wherein the orchiectomy is a subcapsular orchiectomy.
  • Embodiment 26 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 24, wherein the at least one luteinizing hormone-releasing hormone (LHRH) agonist is selected from leuprolide, goserelin, triptorelin and histrelin.
  • LHRH luteinizing hormone-releasing hormone
  • Embodiment 27 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 24, wherein the at least one LHRH antagonist is selected from degarelix and relugolix.
  • Embodiment 28 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is resistant to treatment with an androgen receptor antagonist.
  • Embodiment 29 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 28, wherein the androgen receptor antagonist is selected from flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide.
  • Embodiment 30 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is administered/for administration within one day, two days, three days, four days, five days, six days or one week of the subject exhibiting PSA nadir.
  • Embodiment 31 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is administered/for administration about two weeks, or about three weeks, or about four weeks, or about five weeks after the subject has exhibited PSA nadir, and wherein the PSA level in the subject has increased from PSA nadir.
  • Embodiment 32 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has at least one metabolic dysfunction, wherein the metabolic dysfunction is selected from visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated 14b Ale, or any combination thereof.
  • the metabolic dysfunction is selected from visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated 14b Ale, or any combination thereof.
  • Embodiment 33 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the metabolic dysfunction is a treatment-induced metabolic dysfunction.
  • Embodiment 34 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is selected from:
  • MetAP2 inhibitor is: (Compound 1), or a pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30: 1 to about 3: 1, preferably wherein the ratio of x to y is about 11 : 1.
  • Embodiment 35 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, or pharmaceutically acceptable salt thereof, wherein the MetAP2 inhibitor is administered/for administration to the subject in an amount of: i) about 27 mg/m 2 ; ii) about 36 mg/m 2 ; iii) about 49 mg/m 2 ; or iv) about 65 mg/m 2 .
  • Embodiment 36 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is administered/for administration: i) once every 7 days (Q7D); ii) once every 14 days (Q14D); or iii) once every 21 days (Q21D).
  • Embodiment 37 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, or pharmaceutically acceptable salt thereof, wherein the enzalutamide is administered/for administration to the subject in an amount of: i) about 40 mg; ii) about 80 mg; iii) about 120 mg; or iv) about 160 mg.
  • Embodiment 38 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the enzalutamide is administered/for administration daily.
  • Embodiment 39 The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein administration of the at least one MetAP2 inhibitor results in a reduction in the size of the prostate cancer.
  • Embodiment 40 The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 36, wherein the reduction in the size of the prostate cancer is at least about a 10%, or about a 20%, or about a 30%, or about a 40%, or about a 50%, or about a 60%, or about a 70%, or about an 80%, or about a 90%, or about a 99% reduction in tumor volume.
  • mice were injected subcutaneously with 2xl0 6 LNCaP cells. When tumors reached approximately 200 mm 3 , the mice were split into two treatment groups of four mice each. The first treatment group received Compound 1 in an amount of 12 mg/kg, administered subcutaneously once every 4 days. The second treatment group received a negative control, vehicle treatment comprising 5% mannitol in water.
  • FIG. 1 shows the tumor volume in individual mice (left panel) and the average tumor volume across all mice (right panel) in the Compound 1 and Vehicle control treatment groups.
  • the vertical dashed lines denote the start of treatment.
  • FIG. 2 shows the average PSA levels of mice (left panel) and the endpoint tumor mass (right panel) in the Compound 1 and Vehicle control treatment groups.
  • FIG. 3 shows the body weight of individual mice (left panel) and the average body weight across all mice (right panel) in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment.
  • FIG. 4 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
  • FIG. 5 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
  • FIG. 6 is a graph showing the overall survival of the mice in the Compound 1 and Vehicle control treatment groups. As shown in FIG. 6, treatment with Compound 1 resulted in increased survival of the mice.
  • FIG. 7 shows necropsy images of tumors excised from mice in the Compound 1 and Vehicle control treatment groups.
  • FIG. 8 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 and Vehicle control treatment groups.
  • the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 8, treatment with Compound 1 results in a decrease in tumor vasculature as compared to treatment with the vehicle control.
  • FIG. 9 shows the average tumor volume across all mice in the three treatment groups. The vertical dashed lines denote the start of treatment and the gray box denotes castration.
  • FIG. 10 shows the tumor mass at the conclusion of the study. The results shown in FIGs. 9 and 10 demonstrate that the administration of Compound 1 prevented tumor growth and resulted in smaller tumors at the end of the study.
  • FIG. 11 shows the average PSA levels across all mice in the three treatment groups during the course of the study. The results shown in FIG. 11 demonstrate that PSA levels were not affected by treatment with Compound 1.
  • FIG. 12 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
  • FIG. 13 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
  • FIG. 14 shows average body weight across all mice in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment.
  • the Compound 1 6 mg/kg treatment group is denoted as “Cpdl (6 mpk)” and the Compound 1 12 mg/kg treatment group is denoted as “Cpdl (12 mpk)”.
  • FIG. 15 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the three treatment groups.
  • the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 15, treatment with Compound 1 prevented the formation of tumor vasculature as compared to treatment with the vehicle control.
  • NSG mice prepared as described in Example 2 were subsequently enrolled in one of two treatment groups 2-4 weeks after castration and the recurrence of high PSA levels and tumor growth (i.e., castration-resistant prostate cancer).
  • the first treatment group received Compound 1 in an amount of 12 mg/kg, administered subcutaneously once every 4 days.
  • the second treatment group received a negative control, vehicle treatment comprising 5% mannitol in water(denoted in some figures as “Veh”).
  • FIG. 16 shows the tumor volume in individual mice (top panel) and the average tumor volume across all mice (bottom panel) in the Compound 1 and Vehicle control treatment groups.
  • the vertical dashed lines denote the start of treatment.
  • FIG. 17 shows the endpoint tumor mass (left panel) and average PSA levels of mice (right panel) and in the Compound 1 and Vehicle control treatment groups. As shown in FIGs. 16 and 17, treatment with Compound 1 resulted a decrease in tumor volume while PSA levels were not affected.
  • FIG. 18 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the Compound 1 and Vehicle control treatment groups.
  • the vertical dashed lines denote the start of treatment.
  • FIG. 19 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
  • FIG. 20 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
  • FIG. 21 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 and Vehicle control treatment groups.
  • the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 21, treatment with Compound 1 results in a decrease in tumor vasculature as compared to treatment with the vehicle control.
  • mice prepared as described in Example 2 were subsequently enrolled in one of four treatment groups 2-4 weeks after castration and the recurrence of high PSA levels and tumor growth.
  • the first treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with a negative control, vehicle treatment of 5% mannitol in water.
  • the second treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with Compound 1 in an amount of 12 mg/kg, administered subcutaneously once every 4 days.
  • FIG. 22 shows the average tumor volume across mice in the first treatment group described above.
  • the first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”). Dashed line denotes the start of treatment.
  • FIG. 23 shows the average tumor volume across mice in the first and second treatment groups described above. The first treatment group was stratified into two groups - those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”). Dashed line denotes the start of treatment (enzalutamide or enzalutamide plus Compound 1).
  • FIG. 24 shows the endpoint tumor mass in the first and second treatment groups described above.
  • the first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”).
  • FIG. 25 shows the PSA levels in the first and second treatment groups described above.
  • the first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”). Dashed line denotes the start of treatment (enzalutamide or enzalutamide plus Compound 1).
  • FIG. 26 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the first and second treatment groups described above.
  • the vertical dashed lines denote the start of treatment.
  • FIG. 27 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the first and second treatment groups described above.
  • FIG. 28 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the first and second treatment groups described above.
  • FIG. 29 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the first and second treatment groups described above.
  • the first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”).
  • the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 29, treatment with Compound 1 in combination with enzalutamide results in a decrease in tumor vasculature when compared to enzalutamide alone in the responder group.
  • mice Physically-castrated NSG mice were injected subcutaneously with patient derived castration-resistant prostate cancer tumor samples (LUCAP35CR). When tumors reached ⁇ 250mm 3 , mice were enrolled in one of two treatment groups. The first treatment group received Compound 1 in an amount of 8 mg/kg, administered subcutaneously once every 4 days. The second treatment group received a negative control, vehicle treatment comprising 5% mannitol in water.
  • LUCAP35CR patient derived castration-resistant prostate cancer tumor samples
  • FIG. 30 shows the average tumor volume across all mice in the Compound 1 and Vehicle control treatment groups.
  • the vertical dashed lines denote the start of treatment.
  • FIG. 31 shows the endpoint tumor mass in the Compound 1 and Vehicle control treatment groups. As shown in FIGs. 30 and 31, treatment with Compound 1 resulted in a decrease in tumor volume.
  • FIG. 32 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 and Vehicle control treatment groups.
  • the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 32, treatment with Compound 1 results in a decrease in tumor vasculature as compared to the vehicle control.
  • Transcriptomic analysis of tumor samples from the first and second treatment groups was also performed.
  • FIG. 41 shows the expression levels of particular hypoxia induced, extracellular matrix-related genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIGs. 42A and 42B show the expression levels of particular glycolysis-related genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 43 shows the expression levels of particular serine-glycine one-carbon (SOGC) pathway genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • SOGC serine-glycine one-carbon
  • FIG. 44 shows the expression levels of particular cholesterol uptake and synthesis pathway genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 45 shows the expression levels of particular fatty acid synthesis pathway genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 46 shows the expression levels of particular cell cycle genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 47 shows the expression levels of particular hormone/cytokine receptor genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 48 shows the expression levels of particular kinase genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 49 shows the expression levels of particular transcription factor genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 50 shows the expression levels of particular tumor-inhibiting genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIGs. 51 A and 5 IB show the expression levels of particular tumor-growth promoting/survival genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 52 shows the expression levels of particular nucleotide synthesis genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 53 shows the expression levels of particular lipid metabolism genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 54 shows the expression levels of particular immune recognition genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 55 shows the expression levels of particular immune recognition genes, specifically CD74 ligands and binding partners, in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • FIG. 56 shows the expression levels of particular genes encoding regulators of MHC II, in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
  • Compound 1 Compound 1
  • treatment group 2 vehicle
  • proper stimulation of T cells requires efficient HLA class II antigen presentation by professional or non-professional antigen-presenting cells, including prostate cancer cells.
  • the transcription factor CIITA whose expression is decreased in many cancers, positively regulates the expression of MHC II genes.
  • the enzyme GILT down-regulated in many cancers including prostate cancer, facilitates processing of MHC II-antigen complexes prior to their display on the cell surface.
  • mice treated with Compound 1 was les fibrotic, based on the reduction in multiple collagen genes, and less immunosuppressive, based on the reduction in the expression of Argl.
  • the increased expression of multiple genes involved in adipocyte function indicate increased adipocyte differentiation or hypertrophy, with increased adiponectin potentially exhibiting anti-tumor effects.
  • the left panel in FIG. 35 shows a chart of the number of differentially expressed human genes for each pairwise comparison of treatment groups (see Table A for details on comparison groups). Differential gene expression (DE) is defined by abs.FC > 1.5 and FDR pvalue ⁇ 0.05.
  • the right panel in FIG. 35 shows bubble plots of a selection of significantly enriched (adj .pvalue ⁇ 0.05) cellular pathways from the MSigDB (Molecular Signatures Database) for each of the comparisons presented in Table A and the left panel of FIG. 35.
  • FIGs. 36-40 show bubble plots of genes of interest including LINGO4, SORCS2, KCND3, SNRNP48, GLS, BAG1, AR, KLK3, DDC, STEAP4, FKBP5, FOLH1, PPIA, RAB37, TXN, SH3BGRL, GAPDH, METAP2, R0R2, CTHRC1, DVL3, ARRB2, PPARG, WNT5A, MAPK10, PPKCZ, DVL2, AMACR, PCGEM1, PC A3, PSCA, NIKX3-1, AZGP1, H0XB13, SOX9 and RLN1 for pairwise comparisons of treatment groups (see Table B for details on comparison groups).
  • the first treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with a negative control, vehicle treatment of 5% mannitol in water.
  • the second treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with Compound 1 in an amount of 8 mg/kg, administered subcutaneously once every 4 days.
  • FIG. 33 A shows the average tumor volume across all mice in the two treatment groups
  • the gray box denotes the time period of enzalutamide treatment and the vertical dashed lines denotes the start of resistance to the enzalutamide treatment and start of treatment with Compound 1.
  • FIG. 33B shows the endpoint tumor mass in the first and second treatment groups described above. The results shown in FIGs. 33A and 33B demonstrate that the administration of Compound 1 in combination with enzalutamide prevented tumor growth and resulted in smaller tumors at the end of the study compared to tumors in mice treated with enzalutamide alone.
  • FIG. 33C shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 plus enzalutamide and Vehicle enzalutamide control treatment groups described above.
  • the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 33C, treatment with Compound 1 results in a decrease in tumor vasculature as compared to the vehicle control.
  • AVPC aggressive variant prostate cancer
  • NEPC neuroendocrine prostate cancer
  • LTL545 PDX patient-derived AVPC tumor xenografts (specifically NEPC tumor xenografts) were transplanted into NSG mice. When tumors reached approximately 200 mm 3 , the mice were enrolled in one of two treatments. The first treatment group received Compound 1 in an amount of 8 mg/kg, administered subcutaneously once every 4 days. The second treatment received a negative control, vehicle treatment comprising 5% mannitol in water.
  • FIG. 34A shows the tumor volume of all mice in the two treatment groups and FIG. 34B shows the average tumor volume across all mice in the two treatment groups.
  • the vertical dashed lines denotes the onset of treatment with Compound 1.
  • FIG. 34C shows the endpoint tumor mass in the first and second treatment groups described above.
  • the results shown in FIGs. 34A, 34B and 34C demonstrate that the administration of Compound 1 attenuated AVPC tumor growth and resulted in smaller AVPC tumors at the end of the study.
  • the results presented in this example demonstrate that Compound 1 of the present disclosure can be used to treat AVPC, including NEPC.

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Abstract

The present disclosure provides pharmaceutical combinations comprising MetAP2 inhibitors for the treatment of prostate cancer.

Description

METAP2 INHIBITORS FOR THE TREATMENT OF PROSTATE CANCER
RELATED APPLICATIONS
[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/425,942, filed November 16, 2022, U.S. Provisional Application No. 63/459,077, filed April 13, 2023, and U.S. Provisional Application 63/517,334, filed August 2, 2023. The contents of each of the aforementioned patent applications are incorporated herein by reference in their entireties.
BACKGROUND
[0002] Prostate cancer is the second-most diagnosed malignancy and is the leading cause of cancer death worldwide among men. More specifically, treatment of advanced prostate cancer with androgen deprivation therapy and androgen receptor antagonists (e.g. enzalutamide) has only provided incremental improvements in survival, as patients inevitably develop resistance. Moreover, continuous androgen deprivation or receptor inhibition therapy has been shown to drive systemic metabolic dysfunction, including weight gain, increased insulin resistance, hyperleptinaemia and reduced circulating adiponectin. Such dysfunctions have been shown to lead to molecular reprogramming in tumours that may be in at least in part responsible for the development of treatment resistance. Finally, elevated expression of the enzyme methionine aminopeptidase type 2 (MetAP2) has recently been shown to be associated with higher grade tumours, including neuroendocrine tumours, and worse clinical outcomes.
[0003] Additionally, over the last decade, the clinical approval and increased use of highly potent androgen receptor (AR) pathway inhibitors for the treatment of metastatic castrateresistant prostate cancer (mCRPC) has provided significant improvements in patient survival, but the development of resistance remains a significant clinical issue. In particular, AR inhibition causes major molecular reprograming in tumors, which has resulted in the emergence of highly aggressive and difficult-to-treat molecular subtypes of prostate cancer, termed aggressive variant prostate cancer (AVPC). AVPC is a general term for tumors representing the transition from an adenocarcinoma phenotype, toward less differentiated anaplastic phenotypes, which are driven by alternate non-AR mechanisms to promote tumor growth and survival. Identified in around 30% of mCRPC patients, emerging molecular signatures of AVPC display a spectrum of anaplastic features, including biomarkers of neuroendocrine (NE) disease and lack of AR expression or activity. Few therapeutic options are available for patients at this stage of disease. Patients may receive taxane therapy or, in the wake of encouraging international trials, 177Lutetium-PSMA-617 (Lu-PSMA), a radioligand-based theranostic targeting the cell-surface protein, prostate-specific membrane antigen (PSMA). Nevertheless, -15-30% of patients will not be eligible for Lu-PSMA (or similar targeting agents), especially patients with AVPC metastases characterized as low expression of PSMA by PSMA-PET screening. Therefore, novel, AR-independent therapies are urgently sought for patients with mCRPC and AVPC.
[0004] Thus, there is a need in the art for compositions and methods directed to the treatment of prostate cancer, including treatments that target MetAP2 and/or that mitigate treatment- induced metabolic dysfunctions. The present disclosure provides MetAP2 inhibitors and combinations comprising MetAP2 inhibitors for the treatment of prostate cancer.
SUMMARY
[0005] The present disclosure provides methods of treating prostate cancer in a subject, the methods comprising administering at least one amount of at least one MetAP2 inhibitor to the subject, wherein the MetAP2 inhibitor is:
Figure imgf000004_0001
salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30: 1 to about 3: 1, preferably wherein the ratio of x to y is about 11 : 1, wherein the subject has been previously administered at least one prostate cancer treatment, wherein the prostate cancer treatment comprises androgen deprivation therapy (ADT) and/or at least one androgen receptor antagonist, wherein the prostate cancer has become resistant to treatment with the androgen deprivation therapy (ADT) and/or at least one androgen receptor antagonist, wherein administration of the MetAP2 inhibitor results in reduction in size of the prostate cancer.
[0006] In some aspects, the methods further comprise administering to the subject at least one amount of enzalutamide.
[0007] In some aspects, the prostate cancer is castration-resistant prostate cancer.
[0008] In some aspects, the prostate cancer is castration-sensitive prostate cancer.
[0009] In some aspects, the prostate cancer is androgen receptor-inhibition resistant prostate cancer.
[0010] In some aspects, the prostate cancer is castration-resistant and androgen receptor inhibition-resistant prostate cancer.
[0011] In some aspects, the prostate cancer is PTEN-deficient prostate cancer or partially PTEN-deficient prostate cancer.
[0012] In some aspects, the prostate cancer is PTEN-altered prostate cancer or partially PTEN- altered prostate cancer.
[0013] In some aspects, the prostate cancer is aggressive variant prostate cancer (AVPC).
[0014] In some aspects, the prostate cancer is neuroendocrine prostate cancer (NEPC).
[0015] In some aspects, the androgen deprivation therapy comprises performing an orchiectomy, administering at least one luteinizing hormone-releasing hormone (LHRH) agonist, administering at least one LHRH antagonist, administering at least one estrogen, or any combination thereof. In some aspects, the orchiectomy is a subcapsular orchiectomy. In some aspects, the at least one LHRH agonist is selected from leuprolide, goserelin, triptorelin and histrelin. In some aspects, the at least one LHRH antagonist is selected from degarelix and relugolix.
[0016] In some aspects, the at least one androgen receptor antagonist is selected from flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide, preferably wherein the at least one androgen receptor antagonist is enzalutamide.
[0017] In some aspects, the MetAP2 inhibitor is administered within one day, two days, three days, four days, five days, six days, one week or two weeks of the subject exhibiting PSA nadir. [0018] In some aspects, the MetAP2 inhibitor is administered about two weeks, or about three weeks, or about four weeks, about five weeks, or about six weeks, or about seven weeks, or about eight weeks after the subject has exhibited PSA nadir, and wherein the PSA level in the subject has increased from PSA nadir.
[0019] In some aspects, the subject has at least one metabolic dysfunction, wherein the metabolic dysfunction is selected from visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated HbAlc, or any combination thereof. In some aspects, the metabolic dysfunction is a prostate cancer treatment-induced metabolic dysfunction.
[0020] In some aspects, the MetAP2 inhibitor is administered to the subject in an amount of: i) about 27 mg/m2; ii) about 36 mg/m2; iii) about 49 mg/m2; or iv) about 65 mg/m2.
[0021] In some aspects, MetAP2 inhibitor is administered: i) once every 7 days (Q7D); ii) once every 14 days (Q14D); or iii) once every 21 days (Q21D).
[0022] In some aspects, the enzalutamide is administered to the subject in an amount of: i) about 40 mg; ii) about 80 mg; iii) about 120 mg; or iv) about 160 mg.
[0023] In some aspects, the enzalutamide is administered daily. In some aspects, the enzalutamide is administered weekly.
[0024] Any of the above aspects, or any other aspect described herein, can be combined with any other aspect.
[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the Specification, the singular forms also include the plural unless the context clearly dictates otherwise; as examples, the terms “a,” “an,” and “the” are understood to be singular or plural and the term “or” is understood to be inclusive. By way of example, “an element” means one or more element. Throughout the specification the word “comprising,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”
[0026] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present Specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the disclosure will be apparent from the following detailed description and claim.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The above and further features will be more clearly appreciated from the following detailed description when taken in conjunction with the accompanying drawings.
[0028] FIG. 1 shows the tumor volume in individual mice (left panel) and the average tumor volume across all mice (right panel) in experimental treatment groups described in Example 1.
[0029] FIG. 2 shows the average PSA levels of mice (left panel) and the endpoint tumor mass (right panel) in experimental treatment groups described in Example 1.
[0030] FIG. 3 shows the body weight of individual mice (left panel) and the average body weight across all mice (right panel) in experimental treatment groups described in Example 1. [0031] FIG. 4 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 1.
[0032] FIG. 5 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 1.
[0033] FIG. 6 is a graph showing the overall survival of the mice in experimental treatment groups described in Example 1.
[0034] FIG. 7 shows necropsy images of tumors excised from mice in the experimental treatment groups described in Example 1.
[0035] FIG. 8 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 1.
[0036] FIG. 9 shows the average tumor volume across all mice in the experimental treatment groups described in Example 2.
[0037] FIG. 10 shows the tumor mass at the conclusion of the study in the experimental treatment groups described in Example 2.
[0038] FIG. 11 shows the average PSA levels across all mice during the course of the study in the experimental treatment groups described in Example 2. [0039] FIG. 12 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 2.
[0040] FIG. 13 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 2. [0041] FIG. 14 shows the average body weight across all mice in experimental treatment groups described in Example 2.
[0042] FIG. 15 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 2.
[0043] FIG. 16 shows the tumor volume in individual mice (top panel) and the average tumor volume across all mice (bottom panel) in the experimental treatment groups described in Example 3.
[0044] FIG. 17 shows the endpoint tumor mass (left panel) and average PSA levels of mice (right panel) in the experimental treatment groups described in Example 3.
[0045] FIG. 18 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the experimental treatment groups described in Example 3.
[0046] FIG. 19 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 3.
[0047] FIG. 20 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 3. [0048] FIG. 21 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 3.
[0049] FIG. 22 the average tumor volume in the experimental treatment groups described in Example 4.
[0050] FIG. 23 the average tumor volume in the experimental treatment groups described in Example 4.
[0051] FIG. 24 shows the endpoint tumor mass in the experimental treatment groups described in Example 4.
[0052] FIG. 25 shows the average PSA levels of mice in the experimental treatment groups described in Example 4.
[0053] FIG. 26 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the experimental treatment groups described in Example 4. [0054] FIG. 27 shows the liver, kidney, heart and lung weights at the endpoint of the study in experimental treatment groups described in Example 4.
[0055] FIG. 28 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in experimental treatment groups described in Example 4. [0056] FIG. 29 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 4.
[0057] FIG. 30 shows the average tumor volume in the experimental treatment groups described in Example 5.
[0058] FIG. 31 shows the endpoint tumor mass in the experimental treatment groups described in Example 5.
[0059] FIG. 32 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 5.
[0060] FIG. 33 A is a graph showing average tumor volume across all mice in the two treatment groups described in Example 7.
[0061] FIG. 33B is a graph showing endpoint tumor volume in mice in the two treatment groups described in Example 7.
[0062] FIG. 33C shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the experimental treatment groups described in Example 7.
[0063] FIG. 34A is a graph showing tumor volume of all mice in the two treatment groups described in Example 8.
[0064] FIG. 34B is a graph showing average tumor volume across all mice in the two treatment groups described in Example 8.
[0065] FIG. 34C is a graph showing tumor weight reduction across all mice in the two treatment groups described in Example 8.
[0066] FIG. 35 shows a chart of the number of differentially expressed human genes for each pairwise comparison of treatment groups described in Examples 1-5 (left panel) and bubble plots of a selection of significantly enriched (adj. p value < 0.05) cellular pathways from the MSigDB (Molecular Signatures Database) for each of the comparisons (right panel).
[0067] FIGs. 36, 37, 38, 39 and 40 show bubble plots of genes of interest including for pairwise comparisons of treatment groups described in Examples 1-5.
[0068] FIG. 41 shows the expression levels of particular hypoxia induced, extracellular matrix-related genes in tumor samples from the experimental treatment groups described in Example 5. [0069] FIGs. 42A and 42B show the expression levels of particular glycolysis-related genes in tumor samples from the experimental treatment groups described in Example 5.
[0070] FIG. 43 shows the expression levels of particular serine-glycine one-carbon (SOGC) pathway genes in tumor samples from the experimental treatment groups described in Example 5.
[0071] FIG. 44 shows the expression levels of particular cholesterol uptake and synthesis pathway genes in tumor samples from the experimental treatment groups described in Example 5.
[0072] FIG. 45 shows the expression levels of particular fatty acid synthesis pathway genes in tumor samples from the experimental treatment groups described in Example 5.
[0073] FIG. 46 shows the expression levels of particular cell cycle genes in tumor samples from the experimental treatment groups described in Example 5.
[0074] FIG. 47 shows the expression levels of particular hormone/cytokine receptor genes in tumor samples from the experimental treatment groups described in Example 5.
[0075] FIG. 48 shows the expression levels of particular kinase genes in tumor samples from the experimental treatment groups described in Example 5.
[0076] FIG. 49 shows the expression levels of particular transcription factor genes in tumor samples from the experimental treatment groups described in Example 5.
[0077] FIG. 50 shows the expression levels of particular tumor-inhibiting genes in tumor samples from the experimental treatment groups described in Example 5.
[0078] FIGs. 51 A and 5 IB show the expression levels of particular tumor-growth promoting/survival genes in tumor samples from the experimental treatment groups described in Example 5.
[0079] FIG. 52 shows the expression levels of particular nucleotide synthesis genes in tumor samples from the experimental treatment groups described in Example 5.
[0080] FIG. 53 shows the expression levels of particular lipid metabolism genes in tumor samples from the experimental treatment groups described in Example 5.
[0081] FIG. 54 shows the expression levels of particular immune recognition genes in tumor samples from the experimental treatment groups described in Example 5.
[0082] FIG. 55 shows the expression levels of particular immune recognition genes, specifically CD74 ligands and binding partners, in tumor samples from the experimental treatment groups described in Example 5.
[0083] FIG. 56 shows the expression levels of particular genes encoding regulators of MHC II, in tumor samples from the experimental treatment groups described in Example 5. DETAILED DESCRIPTION
[0084] The present disclosure provides, inter alia, a method of treating prostate cancer comprising administering to a subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, or comprising administering to a subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent.
[0085] Methods and Combinations of the Present Disclosure
[0086] The present disclosure provides methods of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
[0087] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject in need thereof.
[0088] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prostate cancer in a subject in need thereof.
[0089] The present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
[0090] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer in a subject in need thereof.
[0091] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of prostate cancer in a subject in need thereof.
[0092] The present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof. [0093] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence in a subject in need thereof.
[0094] The present disclosure provides the use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of prostate cancer growth or recurrence in a subject in need thereof.
[0095] The present disclosure provides a combination therapy comprising at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[0096] The present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding combination therapy.
[0097] The present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding combination therapy.
[0098] The present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding combination therapy.
[0099] The present disclosure provides a pharmaceutical composition comprising at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00100] The present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding pharmaceutical compositions.
[00101] The present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding pharmaceutical compositions.
[00102] The present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding pharmaceutical compositions. [00103] The present disclosure provides a kit comprising at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00104] The present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding kit.
[00105] The present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding kit.
[00106] The present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject in need thereof at least one amount of the preceding kit.
[00107] The present disclosure provides a method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00108] The present disclosure provides a method of preventing prostate cancer in a subject in need thereof, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00109] The present disclosure provides a method of preventing prostate cancer growth or recurrence in a subject in need thereof, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00110] The present disclosure provides a use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer.
[00111] The present disclosure provides a use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer.
[00112] The present disclosure provides a use of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer growth or recurrence.
[00113] The present disclosure provides a use of enzalutamide, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer.
[00114] The present disclosure provides a use of enzalutamide, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer.
[00115] The present disclosure provides a use of enzalutamide, or a pharmaceutically acceptable salt thereof, in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention of prostate cancer growth or recurrence.
[00116] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of prostate cancer.
[00117] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention of prostate cancer.
[00118] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention of prostate cancer growth or recurrence.
[00119] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in treating prostate cancer. [00120] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer. [00121] The present disclosure provides at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer growth or recurrence.
[00122] The present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in treating prostate cancer.
[00123] The present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer.
[00124] The present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in combination with at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, in preventing prostate cancer growth or recurrence.
[00125] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer.
[00126] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer.
[00127] The present disclosure provides a combination of at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence.
[00128] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer, wherein the combination further comprises enzalutamide, or a pharmaceutically acceptable salt thereof.
[00129] The present disclosure provides a combination comprising enzalutamide, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
[00130] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer, wherein the combination further comprises enzalutamide, or a pharmaceutically acceptable salt thereof.
[00131] The present disclosure provides a combination comprising at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence, wherein the combination further comprises enzalutamide, or a pharmaceutically acceptable salt thereof.
[00132] The present disclosure provides a combination comprising enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
[00133] The present disclosure provides a combination comprising enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence, wherein the combination further comprises at least one MetAP2 inhibitor of the present disclosure, or a pharmaceutically acceptable salt thereof.
[00134] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof [00135] The present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer, wherein the method further comprises administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.
[00136] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof. [00137] The present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer, wherein the method further comprises administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof. [00138] The present disclosure provides a MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00139] The present disclosure provides enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence, wherein the method further comprises administration of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof.
[00140] In some aspects, a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof, can be administered by the same administration route.
[00141] In some aspects, a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof, can be administered by different administration routes.
[00142] In some aspects, a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof, can be administered concurrently. [00143] In some aspects, a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof, can be administered in temporal proximity.
[00144] In some aspects, a MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and enzalutamide, or pharmaceutically acceptable salt thereof, can be administered in any order.
[00145] In some aspects of the methods and uses presented herein, the administration of a MetAP2 inhibitor and/or the administration of a MetAP2 inhibitor in combination with enzalutamide, results in a decrease in angiogenesis in at least one tumor in the subject. In some aspects, the decrease is at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, at least a 95%, or at least a 99% decrease in angiogenesis.
[00146] In some aspects of the methods and uses presented herein, the administration of a MetAP2 inhibitor and/or the administration of a MetAP2 inhibitor in combination with enzalutamide, results in a decrease in the expression level of at least one gene selected from P4HA1, LOX, GLUT1/SLC2A1, HK2, PDK1FKFB3, FKFB4, PKM, ENO1, LDHA, GLS, PHGDH, SHMT2, TYMS, PSPH, LDL receptor, SQLE, HMGCR, ACACA, ACLY, SCD, CCNB1, CXCR4, FZD8, FZD3, IGFlr, MAP2K6, MAPK13, AURKA, AURKB, EZH2, F0XM1, MYB, SREBF1, MYBL2, BIRC5, ANTRX1, DPYLS3, HMMR, BAG1, Ki67, CCNB1, PCLAF, TK1, RRM2, TK1, RRM1, RRM2, PLA2G2A, MIF, CXCR4 and CD44. In some aspects, the decrease is at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, at least a 95%, or at least a 99% decrease in expression.
[00147] In some aspects of the methods and uses presented herein, the administration of a MetAP2 inhibitor and/or the administration of a MetAP2 inhibitor in combination with enzalutamide, results in an increase in the expression level of at least one gene selected from CDKN2B, PIK3IP1, SH3BGRL2, CD 177, HLA-DRA, HLA-E, HLA-DMA, HLA-DMB, CD74, CIITA, IFI30. In some aspects, the increase is at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, at least a 90%, at least a 95%, or at least a 99% increase in expression.
[00148] MetAP2 inhibitors
[00149] Any of the MetAP2 inhibitors described herein can be used in the kits, pharmaceutical compositions, uses and methods described herein.
[00150] In some aspects, a MetAP2 inhibitor can be Compound 1, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 1 is represented by:
Figure imgf000019_0001
about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100. In some aspects, n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50. In some aspects, the ratio of x to y can be in the range of about 30: 1 to about 3: 1.
[00151] In some aspects, a MetAP2 inhibitor can be Compound 2, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 2 is represented by:
Figure imgf000020_0001
is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100. In some aspects, n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50. In some aspects, the ratio of x to y can be in the range of about 30:1 to about 3: 1.
[00152] In some aspects, a MetAP2 inhibitor can be Compound 3, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 3 is represented
Figure imgf000021_0001
about 100. In some aspects, n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50. In some aspects, the ratio of x to y can be in the range of about 30:1 to about 3: 1.
[00153] In some aspects, a MetAP2 inhibitor can be Compound 4, or a pharmaceutically acceptable salt, analog, derivative, salt or ester thereof, wherein Compound 4 is represented by:
Figure imgf000022_0001
(Compound 4) , wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100. In some aspects, n is in the range of about 1 to about 90; about 1 to about 80; about 1 to about 70; about 1 to about 60; about 1 to about 55; or about 1 to about 50. In some aspects, the ratio of x to y can be in the range of about 30:1 to about 3: 1.
[00154] In some aspects, the MetAP2 inhibitor can be:
Figure imgf000022_0002
derivative, salt or ester thereof.
[00155] In some aspects, the MetAP2 inhibitor can be:
Figure imgf000023_0001
pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.
[00156] In some aspects, the MetAP2 inhibitor can be:
Figure imgf000023_0002
salt, analog, derivative, salt or ester thereof.
[00157] In some aspects, the MetAP2 inhibitor can be:
Figure imgf000023_0003
[00158] In some aspects, the MetAP2 inhibitor can be:
Figure imgf000023_0004
pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.
[00159] In some aspects, the MetAP2 inhibitor can be selected from cis-(3aRS,9bRS)-7-
(benzenesulfonylamino)-l,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3 aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-l,3a,4,9b- tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin- l-yl}propyl)-4-fluorobenzenesulfonylamino]-l,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-
6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-l-enyl)-4- fluorobenzenesulfonylamino]-l,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aR,9bR)-7-[2-((Z)-3-diethylaminoprop-l-enyl)-4-fluoro-benzenesulfonylamino]- l,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aS,9bS)-7-[2-((Z)-3- diethylaminoprop-l-enyl)-4-fluorobenzenesulfonylamino]-l,3a,4,9b-tetrahydro-2H-furo[2,3- c]chromene-6-carboxylic acid; 7-[2-((Z)-3-diethylaminoprop-l-enyl)-4- fluorobenzenesulfonylamino]-l,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate salt; 7-(benzenesulfonylamino))-l,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid formate salt; cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-l-enyl)-4-fluorobenzenesulfonylamino]- l,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid; (1 aRS,7bSR)-5-[2-((Z)-3- di ethylaminoprop- 1 -enyl)-4-fluorobenzenesulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laR,7bS)-5-[2-((Z)-3- di ethylaminoprop- 1 -enyl)-4-fluorobenzenesulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aS,7bR)-5-[2-((Z)-3- di ethylaminoprop- 1 -enyl)-4-fluorobenzenesulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-((Z)-3- diethylaminoprop-l-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-l, 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-((E)-3- di ethylaminoprop- l-enyl)-4-fhiorobenzenesulfonylamino]-7b-methyl- 1,1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(4- dimethylamino-butylamino)-benzenesulfonylamino]-l,3a,4,9b-tetrahydro-2H-furo[2,3- c]chromene-6-carboxylic acid; (1 aR,7bS)-5-[2-(3-diethylaminopropyl)-4- fluorobenzenesulfonyl-amino]-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-l-enyl)-4-fluorobenzene-sulfonylamino]- 1 , 1 -difluoro- 1 , 1 a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; ( 1 aR,7b S)-5-[2- ((Z)-3-diethylaminoprop-l-enyl)-4-fluorobenzene-sulfonylamino]-l,l-difluoro-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aS,7bR)-5-[2-((Z)-3- di ethylaminoprop- 1 -enyl)-4-fluorobenzene-sulfonylamino]- 1 , 1 -difluoro- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2((Z)-3- ethylaminoprop- 1 -enyl)-4-fluoro-benzenesulfonylamino]- 1 , 1 a,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid; (laR,7bS)-5-[2((Z)-3-ethylaminoprop-l-enyl)-4- fluorobenzenesulfonylamino]-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; ( 1 aS,7bR)-5-[2((Z)-3 -ethylaminoprop- 1 -enyl)-4-fluorobenzene-sulfonylamino]- 1 , 1 a, 2,7b- tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-l- yl)prop- 1 -enyl]-4-fhiorobenzenesulfonylamino}-l , 1 a,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid; (laR,7bS)-5-{2[(Z)-3-(pyrrolidin-l-yl)prop-l- enyl]-4-fluorobenzenesulfonyl-amino}-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4- carboxylic acid; (1 aS,7bR)-5-{2 [(Z)-3-(pyrrolidin-l-yl)prop-l-enyl]-4- fluorobenzenesulfonylamino}-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aR,7bS)-5-[2-(3- dimethylaminopropylamino)benzene-sulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laS,7bR)-5-[2-(3- dimethylaminopropyl-amino)benzenesulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-(4- dimethylaminobutylamino)benzenesulfonylamino]-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laR,7bS)-5-[2-(4-dimethylamino- butylamino)benzenesulfonylamino]-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylic acid; (laS,7bR)-5-[2-(4-dimethylaminobutylamino]-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-[2-(5-dimethylamino- pentylamino)benzene-sulfonylamino]-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylic acid; (laRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-l-enyl]-4- fluorobenzenesulfonyl-amino}-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidin-l-yl)aminoprop-l-enyl]-4- fluorobenzenesulfonylamino}-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2[(Z)-3-((R)-3-hydroxypyrrolidin-l-yl)aminoprop-l-enyl]-4- fluorobenzene-sulfonylamino}-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2((Z)-4-diethylaminobut-l-enyl)-4-fluorobenzenesulfonyl-amino]- 1, la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laR,7bS)-5-[2((Z)-4- diethylaminobut- 1 -enyl)-4-fluorobenzenesulfonyl-amino]- 1 , 1 a, 2, 7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aS,7bR)-5-[2((Z)-4-diethylaminobut- l-enyl)-4-fluorobenzenesulfonyl-amino]-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4- carboxylic acid; (1 aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-l-yl)-ethyl]-4- fluorobenzenesulfonylamino}-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2[(Z)-3-(azetidin-l-yl)prop-l-enyl]-4-fluorobenzene-sulfonylamino}- l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2[(Z)-3-(3- hydroxy-azetidin- 1 -yl)prop- 1 -enyl]-4-fluorobenzene-sulfonylamino} - 1 , 1 a, 2,7b- tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2[(Z)-3-(azetidin-l- yl)propyl]-4-fluorobenzenesulfonylamino}-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4- carboxylic acid; (1 aRS,7bSR)-5-[2((Z)-4-diethylaminobutyl)-4- fluorobenzenesulfonylamino]-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonyl-amino}- l,la,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[((S)-l- ethylpyrrolidin-3-ylcarbamoyl)-methyl]-4-fluoro-benzenesulfonyl-amino}-l,la,2,7b- tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-(l-ethylazetidin-3- yl)-4-fluorobenzenesulfonylamino]-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4- carboxylic acid; (1 aRS,7bSR)-5-{2-[((R)-l-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4- fluorobenzenesulfonyl-amino}-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-(pyrrolidin-l-yl)-ethyl]-4-fluorobenzenesulfonylamino}- 1, la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-((R)-l- ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-l,la,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid; (laS,7bR)-5-[2-((R)-l-ethylpyrrolidin-3- ylmethyl)-4-fluorobenzenesulfonyl-amino]-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4- carboxylic acid; (1 aR,7bS)-5-[2-((R)-l-ethylpyrrolidin-3-ylmethyl)-4- fluorobenzenesulfonyl-amino]-l,la,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[((S)-l-ethylpyrrolidin-2-yl)carbonyl-aminomethyl]-4- fluorobenzene-sulfonylamino}-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]- l,la,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-((S)-l- ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-(3- dimethylaminopropylcarbamoyl)benzene-sulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-(2-{[N-((S)-l-ethyl- pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-l,la,2,7b- tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-(2-{[N-((R)-l-ethyl- pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-l,la,2,7b- tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-((S)-l- ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-l,la,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[2-((R)-l-ethylpyrrolidin-2- yl)ethylamino]-benzenesulfonyl-amino}-l,la,2,7b-tetrahydrocyclopropa-[c]chromene-4- carboxylic acid; (laRS,7bSR)-5-[2-(3-N,N,-diethylaminopropylamino)benzene- sulfonylamino]-l, la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)- 5-(2-{[((R)-l-ethylpyrrolidine-2-yl)carbonyl-amino]methyl}-4- fluorobenzenesulfonylamino)-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[(l-ethylazetidin-3-ylmethyl)amino]benzene-sulfonylamino}-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aS,7bR)-5-[2-((Z)-3- di ethylaminoprop- 1 -enyl)benzenesulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aR,7bS)-5-[2-((Z)-3- di ethylaminoprop- 1 -enyl)benzenesulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-(2-{N-[((R)-l- ethylpyrrolidine-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)- l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-(2-{N-[((S)- l-ethylpyrrolidine-2-yl)carbonyl]-N-methylamino-methyl}-4-fluorobenzenesulfonylamino)- l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-[2-(4- dimethylaminobutylamino)-4-fluorobenzenesulfonyl-amino]-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[((R)-l- ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-l,la,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[((S)-l-ethylpyrrolidin-3- ylmethyl)amino]-benzenesulfonylamino}-l,la,2,7b-tetrahydrocyclopropa-[c]chromene-4- carboxylic acid; (laRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-l-ylmethyl)-4-fluorobenzene- sulfonylamino]-l, la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)- 5-[2-(l-ethylpiperidin-4-ylmethyl)-4-fluoro-benzenesulfonylamino]-l,la,2,7b- tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-(l- ethylazetidin-3-yl)ethyl]-4-fluoro-benzenesulfonyl-amino}-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[((S)-l- azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-l,la,2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[((R)-l-azabicyclo- [2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-l,la,2,7b-tetrahydrocyclopropa[c]chromene- 4-carboxylic acid; (1 aRS,7bSR)-5-(2-{[((S)-l-ethylpyrrolidine-3-carbonyl)amino]methyl}- 4-fluoro-benzenesulfonylamino)-l,la,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-((R)-l-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro- benzenesulfonylamino}-l, la,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[((R)-l-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-l,la,2,7b- tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[((S)-l- ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-l,la,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-(2-{[((R)-l-ethylpyrrolidine-3- carbonyl)amino]-methyl)}-4-fluoro-benzenesulfonylamino)-l,la,2,7b-tetrahydro- cyclopropa[c]chromene-4-carboxylic acid; (laRS,7bSR)-5-[2-((Z)-3-diethylamino-2- methylprop- 1 -enyl)-4-fluorobenzene-sulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1 aRS,7bSR)-5-{2-[2-((R)-l- ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-l,la,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid; (laRS,7bSR)-5-{2-[2-((S)-l-ethylpyrrolidin-3- yl)ethylamino]-benzenesulfonyl-amino}-l,la,2,7b-tetrahydrocyclopropa-[c]chromene-4- carboxylic acid; (laR,7bS)-5-[2-((S)-l-ethylpyrrolidin-3-yloxymethyl)-4-fluoro- benzenesulfonylamino]-l, la,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (1 aR,7bS)-5-[2-((R)-l-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]- l,la,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid; (laR,7bS)-5-[2-(l- ethylpiperi din-3 -ylmethyl)-4-fluorobenzene-sulfonylamino]- 1 , 1 a, 2,7b- tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (laR,7bS)-5-{2-[2-((R)-l- ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonyl-amino}-l,la,2,7b-tetrahydrocyclopropa- [c]chromene-4-carboxylic acid; and pharmaceutically acceptable salts, stereoisomers, esters and prodrugs thereof.
[00160] In some aspects, a MetAP2 inhibitor can be selected from:
Figure imgf000028_0001
Figure imgf000029_0001
pharmaceutically acceptable salt, analog, derivative, salt or ester thereof. [00161] In some aspects, a MetAP2 inhibitor can be:
Figure imgf000030_0001
pharmaceutically acceptable salt, analog, derivative, salt or ester thereof.
[00162] In some aspects, a MetAP2 inhibitor can be administered by subcutaneous injection (SC). In some aspects, a MetAP2 inhibitor can be administered by subcutaneous injection to the mid-abdominal (per-umbilical area). In some aspects, a subcutaneous injection of a MetAP2 inhibitor can be administered over an about 30 to about 45 second timeframe at a constant injection rate. In some aspects, the maximum injection volume of a MetAP2 inhibitor is less than about 1.7 ml.
[00163] In some aspects, a MetAP2 inhibitor can be administered about every four days (Q4D).
[00164] In some aspects, a MetAP2 inhibitor can be administered about once every day (QD), about once every two days (Q2D), about once every three days (Q3D), about once every four days (Q4D), about once every 5 days (Q5D), about once every 6 days (Q6D), about once every 7 days (Q7D), about once every 8 days (Q8D), about once every 9 days (Q9D), about once every 10 days (Q10D), about once every 11 days (QI ID), about once every 12 days (QI 2D), about once every 13 days (QI 3D), about once every 14 days (Q14D), or about once every 15 days (Q15D). In some aspects, a MetAP2 inhibitor can be administered about once every 7 days (Q7D). In some aspects, a MetAP2 inhibitor can be administered about once every 14 days (Q14D).
[00165] In some aspects, an amount of a MetAP2 inhibitor can be a therapeutically effective amount of a MetAP2 inhibitor.
[00166] In some aspects, a MetAP2 inhibitor can be administered in an amount of about 1 mg/m2, or about 2 mg/m2, or about 3 mg/m2, or about 4 mg/m2, or about 5 mg/m2, or about 6 mg/m2, or about 7 mg/m2, or about 8 mg/m2, or about 9 mg/m2, or about 10 mg/m2, or about 11 mg/m2, or about 12 mg/m2, or about 13 mg/m2, or about 14 mg/m2, or about 15 mg/m2, or about 16 mg/m2, or about 17 mg/m2, or about 18 mg/m2, or about 19 mg/m2, or about 20 mg/m2, or about 21 mg/m2, or about 22 mg/m2, or about 23 mg/m2, or about 24 mg/m2, or about 25 mg/m2, or about 26 mg/m2, or about 27 mg/m2, or about 28 mg/m2, or about 29 mg/m2, or about 30 mg/m2, or about 31 mg/m2, or about 32 mg/m2, or about 33 mg/m2, or about 34 mg/m2, or about 35 mg/m2, or about 36 mg/m2, or about 37 mg/m2, or about 38 mg/m2, or about 39 mg/m2, or about 40 mg/m2, or about 41 mg/m2, or about 42 mg/m2, or about 43 mg/m2, or about 44 mg/m2, or about 45 mg/m2, or about 46 mg/m2, or about 47 mg/m2, or about 48 mg/m2, or about 49 mg/m2, or about 50 mg/m2, or about 51 mg/m2, or about 52 mg/m2, or about 53 mg/m2, or about 54 mg/m2, or about 55 mg/m2, or about 56 mg/m2, or about 57 mg/m2, or about 58 mg/m2, or about 59 mg/m2, or about 60 mg/m2, or about mg/m2, or about 61 mg/m2, or about 62 mg/m2, or about 63 mg/m2, or about 64 mg/m2, or about 65 mg/m2, or about 66 mg/m2, or about 67 mg/m2, or about 68 mg/m2, or about 69 mg/m2, or about 70 mg/m2, or about 81 mg/m2, or about 82 mg/m2, or about 83 mg/m2, or about 84 mg/m2, or about 85 mg/m2, or about 86 mg/m2, or about 87 mg/m2, or about 88 mg/m2, or about 89 mg/m2, or about 90 mg/m2, or about 91 mg/m2, or about 92 mg/m2, or about 93 mg/m2, or about 94 mg/m2, or about 95 mg/m2, or about 96 mg/m2, or about 97 mg/m2, or about 98 mg/m2, or about 99 mg/m2, or about 100 mg/m2.
[00167] In some aspects, a MetAP2 inhibitor can be administered in an amount of about 49 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 36 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 65 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 27 mg/m2.
[00168] In some aspects, a MetAP2 inhibitor can be administered in an amount of about 49 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 39 mg/m2 to about 59 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 44 mg/m2 to about 54 mg/m2.
[00169] In some aspects, a MetAP2 inhibitor can be administered in an amount of about 36 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 26 mg/m2 to about 49 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 31 mg/m2 to about 65 mg/m2.
[00170] In some aspects, a MetAP2 inhibitor can be administered in an amount of about 65 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 55 mg/m2 to about 75 mg/m2. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 60 mg/m2 to about 70 mg/m2.
[00171] In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 1 mg/m2, or about 2 mg/m2, or about 3 mg/m2, or about 4 mg/m2, or about 5 mg/m2, or about 6 mg/m2, or about 7 mg/m2, or about 8 mg/m2, or about 9 mg/m2, or about 10 mg/m2, or about 11 mg/m2, or about 12 mg/m2, or about 13 mg/m2, or about 14 mg/m2, or about 15 mg/m2, or about 16 mg/m2, or about 17 mg/m2, or about 18 mg/m2, or about 19 mg/m2, or about 20 mg/m2, or about 21 mg/m2, or about 22 mg/m2, or about 23 mg/m2, or about 24 mg/m2, or about 25 mg/m2, or about 26 mg/m2, or about 27 mg/m2, or about 28 mg/m2, or about 29 mg/m2, or about 30 mg/m2, or about 31 mg/m2, or about 32 mg/m2, or about 33 mg/m2, or about 34 mg/m2, or about 35 mg/m2, or about 36 mg/m2, or about 37 mg/m2, or about 38 mg/m2, or about 39 mg/m2, or about 40 mg/m2, or about 41 mg/m2, or about 42 mg/m2, or about 43 mg/m2, or about 44 mg/m2, or about 45 mg/m2, or about 46 mg/m2, or about 47 mg/m2, or about 48 mg/m2, or about 49 mg/m2, or about 50 mg/m2, or about 51 mg/m2, or about 52 mg/m2, or about 53 mg/m2, or about 54 mg/m2, or about 55 mg/m2, or about 56 mg/m2, or about 57 mg/m2, or about 58 mg/m2, or about 59 mg/m2, or about 60 mg/m2, or about mg/m2, or about 61 mg/m2, or about 62 mg/m2, or about 63 mg/m2, or about 64 mg/m2, or about 65 mg/m2, or about 66 mg/m2, or about 67 mg/m2, or about 68 mg/m2, or about 69 mg/m2, or about 70 mg/m2, or about 81 mg/m2, or about 82 mg/m2, or about 83 mg/m2, or about 84 mg/m2, or about 85 mg/m2, or about 86 mg/m2, or about 87 mg/m2, or about 88 mg/m2, or about 89 mg/m2, or about 90 mg/m2, or about 91 mg/m2, or about 92 mg/m2, or about 93 mg/m2, or about 94 mg/m2, or about 95 mg/m2, or about 96 mg/m2, or about 97 mg/m2, or about 98 mg/m2, or about 99 mg/m2, or about 100 mg/m2.
[00172] In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 49 mg/m2. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 39 mg/m2 to about 59 mg/m2. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 44 mg/m2 to about 54 mg/m2.
[00173] In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 36 mg/m2. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 26 mg/m2 to about 49 mg/m2. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 31 mg/m2 to about 49 mg/m2.
[00174] In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 65 mg/m2. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 55 mg/m2 to about 75 mg/m2. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 60 mg/m2 to about 70 mg/m2.
[00175] In some aspects, a MetAP2 inhibitor can be administered in an amount of about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg or about 110 mg, or about 120 mg, or about 130 mg, or about 140 mg, or about 150 mg, or about 160 mg, or about 170 mg, or about 180 mg, or about 190 mg, or about 200 mg. In some aspects a MetAP2 inhibitor can be administered in an amount of about 80 mg. In some aspects, a MetAP2 inhibitor can be administered in an amount of about of about 70 mg to about 90 mg. In some aspects, a MetAP2 inhibitor can be administered in an amount of about 75 mg to about 85 mg. [00176] In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg. In some aspects a therapeutically effective amount of a MetAP2 inhibitor can be about 80 mg. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about of about 70 mg to about 90 mg. In some aspects, a therapeutically effective amount of a MetAP2 inhibitor can be about 75 mg to about 85 mg.
[00177] Enzalutamide
[00178] As would be appreciated by the skilled artisan, enzalutamide has the following chemical structure:
Figure imgf000033_0001
[00179] As would be appreciated by the skilled artisan, it is understood that enzalutamide may be identified by any of the following names: 4-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5- dimethyl-4-oxo-2-thioxo-l-imidazolidinyl]-2-fluoro-7V-methylbenzamide, MDV 3100, Xtandi, and S -Enzalutamide. As would be appreciated by the skilled artisan, enzalutamide may be identified as CAS No. 915087-33-1. In the figures accompanying the present disclosure, enzalutamide may be abbreviated “ENZ” or “Enz”.
[00180] In some aspects, enzalutamide can be administered orally.
[00181] In some aspects, an amount of enzalutamide can be a therapeutically effective amount of enzalutamide.
[00182] In some aspects, an amount of enzalutamide can be any of the amounts listed below. [00183] In some aspects, enzalutamide can be administered in an amount of about 20 mg, or about 40 mg, or about 60 mg, or about 80 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg, or about 180 mg, or about 200 mg, or about 220 mg, or about 240 mg, or about 260 mg, or about 280 mg, or about 300 mg, or about 320 mg, or about 340 mg, or about 360 mg, or about 380 mg, or about 400 mg, or about 420 mg, or about 440 mg, or about 460 mg, or about 480 mg, or about 500 mg.
[00184] In some aspects, enzalutamide can be administered in an amount of about 160 mg. In aspects wherein enzalutamide is administered in an amount of about 160 mg, the amount can be administered by orally administering four capsules of 160 mg.
[00185] In some aspects, a therapeutically effective amount of enzalutamide can be any of the enzalutamide amounts described herein.
[00186] In some aspects, enzalutamide can be administered as a pharmaceutical composition, wherein the pharmaceutical composition comprises capryl ocaproyl polyoxylglycerides. In some aspects, the pharmaceutical composition can comprise at least one of caprylocaproyl polyoxylglycerides, butylated hydroxy anisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide [00187] In some aspects, enzalutamide can be administered about once a day.
[00188] Prostate Cancer
[00189] The terms "cancer" and ’’cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
[00190] In some aspects, the prostate cancer can be androgen receptor-positive (AR+) prostate cancer.
[00191] In some aspects, the prostate cancer is androgen sensitive prostate cancer. In some aspects, the prostate cancer is a prostate cancer that has reverted to an androgen sensitive state from an androgen-insensitive state.
[00192] In some aspects, the prostate cancer can be castration-resistant prostate cancer.
[00193] In some aspects, the prostate cancer is castration-sensitive prostate cancer.
[00194] In some aspects, the prostate cancer is metastatic.
[00195] In some aspects, the prostate cancer can be phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-deficient prostate cancer. In some aspects, the prostate cancer can be partially PTEN-deficient prostate cancer.
[00196] In some aspects, the prostate cancer can be PTEN-altered prostate cancer. In some aspects, the prostate cancer can be partially PTEN-altered prostate cancer.
[00197] In some aspects, the prostate cancer is metastatic prostate cancer. [00198] In some aspects, the prostate cancer is advanced prostate cancer.
[00199] In some aspects, the prostate cancer is aggressive variant prostate cancer (AVPC). [00200] In some aspects, the prostate cancer is neuroendocrine prostate cancer (NEPC). [00201] In some aspects, the prostate cancer is resistant to treatment using androgen deprivation therapy (ADT). In some aspects, the prostate cancer has progressed while the subject has been on a treatment regimen comprising the administration of at least one ADT. [00202] As would be appreciated by the skilled artisan, ADT can include, but is not limited to, performing an orchiectomy, administering at least one luteinizing hormone-releasing hormone (LHRH) agonist, administering at least one LHRH antagonist, administering at least one estrogen, or any combination thereof.
[00203] As would be appreciated by the skilled artisan, an orchiectomy can comprise the removal or one or two testicles from a subject. In some aspects, an orchiectomy can be a subcapsular orchiectomy, wherein only the tissues in the testicles that produce androgen are removed, rather than the entire testicle.
[00204] As would be appreciated by the skilled artisan, LHRH agonists include, but are not limited to, leuprolide, goserelin, triptorelin and histrelin.
[00205] As would be appreciated by the skilled artisan, LHRH antagonists include, but are not limited to, degarelix and relugolix.
[00206] In some aspects, the prostate cancer is resistant to treatment using an androgen receptor antagonist or inhibitor. In some aspects, the prostate cancer has progressed while the subject has been on a treatment regimen comprising the administration of at least one androgen receptor antagonist or inhibitor.
[00207] As would be appreciated by the skilled artisan, androgen receptor antagonists or inhibitors include, but are not limited to flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide.
[00208] In some aspects, the prostate cancer is resistant to treatment using enzalutamide.
[00209] In some aspects, the prostate cancer has progressed while the subject has been on a treatment regimen comprising the administration of enzalutamide.
[00210] Any of the above prostate cancer characteristics can be combined. Thus, in a nonlimiting example, the prostate cancer can be PTEN-deficient, castration resistant prostate cancer.
[00211] Subjects
[00212] In some aspects, the subject in need thereof is an animal. In some aspects, the animal can be a mammal. In some aspects, the subject in need thereof is a human. [00213] In some aspects, the subject in need thereof is a human of 18 years or older, or of 25 years or older, or of 50 years or older, or of 60 years or older, or of 65 years or older, or of 70 years or older, or of 75 years or older, or of 80 years or older, or of 85 years or older.
[00214] In some aspects, the subject has been previously administered at least one androgen deprivation therapy (ADT).
[00215] In some aspects, the subject has been previously administered at least one androgen receptor antagonist.
[00216] In some aspects, the subject has been previously administered at least one androgen receptor antagonist and at least one androgen deprivation therapy.
[00217] In some aspects, a subject in need thereof has at least one metabolic dysfunction. In some aspects, the at least one metabolic dysfunction can be excessive visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated HbAlc, or any combination thereof.
[00218] In some aspects the at least one metabolic dysfunction is a treatment-induced metabolic dysfunction. In a non-limiting example, the metabolic dysfunction is a treatment- induced metabolic dysfunction that is induced by the treatment with at least one androgen deprivation therapy and/or at least one androgen receptor antagonist.
[00219] General Definitions
[00220] Certain compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-i somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure. Any representation of a particular isomer is merely exemplary (e.g., the exemplification of a trans-isomer, also encompasses a cis-isomer).
[00221] If, for instance, a particular enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomer.
[00222] In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present disclosure includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like. In addition, a crystal polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present disclosure. Furthermore, so-called metabolite which is produced by degradation of the present compound in vivo is included in the scope of the present disclosure.
[00223] “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture”.
[00224] A carbon atom bonded to four nonidentical substituents is termed a “chiral center”. [00225] “Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
[00226] “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
[00227] Furthermore, the structures and other compounds discussed in this disclosure include all atropic isomers thereof. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques; it has been possible to separate mixtures of two atropic isomers in select cases.
[00228] “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
[00229] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ringchain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ringshaped) form as exhibited by glucose.
[00230] Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide- imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine.
[00231] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form.
[00232] The term “crystal polymorphs”, “polymorphs” or “crystal forms” means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions. [00233] Additionally, the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
[00234] “Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.
[00235] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
[00236] As defined herein, the term “derivative” refers to compounds that have a common core structure, and are substituted with various groups as described herein.
[00237] The term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, (Rem. Rev. 96, 3147-3176, 1996.
[00238] As used herein, the term “temporal proximity” refers to that administration of one therapeutic agent (e.g., a MetAP2 inhibitor compound disclosed herein) occurs within a time period before or after the administration of another therapeutic agent (e.g., enzalutamide), such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, the therapeutic effect of the one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the other therapeutic agent. “Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered. In some embodiments, “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within a week, within 2 weeks, within 3 weeks, within 4 weeks, with 6 weeks, or within 8 weeks. In some embodiments, multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may change during a treatment cycle or within a dosing regimen.
[00239] The terms “effective amount” and “therapeutically effective amount” of an agent or compound are used in the broadest sense to refer to a nontoxic but sufficient amount of an active agent or compound to provide the desired effect or benefit.
[00240] The term "benefit" is used in the broadest sense and refers to any desirable effect and specifically includes clinical benefit as defined herein. Clinical benefit can be measured by assessing various endpoints, e.g., inhibition, to some extent, of disease progression, including slowing down and/or complete arrest; reduction in the number of disease episodes and/or symptoms; reduction in lesion size; inhibition (i.e., reduction, slowing down or complete stopping) of disease cell infiltration into adjacent peripheral organs and/or tissues; inhibition (i.e. reduction, slowing down or complete stopping) of disease spread; decrease of autoimmune response, which may, but does not have to, result in the regression or ablation of the disease lesion; relief, to some extent, of one or more symptoms associated with the disorder; increase in the length of disease-free presentation following treatment, e.g., progression-free survival; increased overall survival; higher response rate; decreased mortality at a given point of time following treatment; and/or improvement in one of the following symptoms: congestion, fluid/edema, wheezing, coughing, hypoxemia, low oxygen saturation, lung stiffness, shortness of breath, shortness of breath during exercise, dry hacking cough, fast shallow breathing, weight loss, tiredness, aching joints, aching muscles and clubbing. [00241] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[00242] As used herein, the term “combination therapy” or “co-therapy” includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
[00243] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.
[00244] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment or prophylaxis as is described herein, as well as use of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.
[00245] As used herein, the term “subject” is interchangeable with the term “subject in need thereof’, both of which refer to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human.
[00246] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. [00247] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
[00248] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
[00249] Exemplary Embodiments
[00250] Embodiment la. A method of treating prostate cancer in a subject, the method comprising administering at least one amount of at least one MetAP2 inhibitor to the subject.
[00251] Embodiment lb. A method of preventing prostate cancer in a subject, the method comprising administering at least one amount of at least one MetAP2 inhibitor to the subject.
[00252] Embodiment 1c. A method of preventing prostate cancer growth or recurrence in a subject, the method comprising administering at least one amount of at least one MetAP2 inhibitor to the subject.
[00253] Embodiment 2a. A MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject.
[00254] Embodiment 2b. A MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, for use in preventing prostate cancer in a subject.
[00255] Embodiment 2c. A MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence in a subject.
[00256] Embodiment 3a. A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in treating prostate cancer in a subject.
[00257] Embodiment 3b. A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer in a subject.
[00258] Embodiment 3c. A combination comprising at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in preventing prostate cancer growth or recurrence in a subject.
[00259] Embodiment 4a. A method of treating prostate cancer in a subject, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of enzalutamide, or a pharmaceutically acceptable salt thereof. [00260] Embodiment 4b. A method of preventing prostate cancer in a subject, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00261] Embodiment 4c. A method of preventing prostate cancer growth or recurrence in a subject, the method comprising administering to the subject at least one amount of at least one MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, and at least one therapeutically effective amount of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00262] Embodiment 5a. A MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00263] Embodiment 5b. A MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer in a subject, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00264] Embodiment 5c. A MetAP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence in a subject, wherein the method further comprises administration of enzalutamide, or a pharmaceutically acceptable salt thereof.
[00265] Embodiment 6a. Enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of treating prostate cancer in a subject, wherein the method further comprises administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof. [00266] Embodiment 6b. Enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer in a subject, wherein the method further comprises administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof. [00267] Embodiment 6c. Enzalutamide, or a pharmaceutically acceptable salt thereof, for use in a method of preventing prostate cancer growth or recurrence in a subject, wherein the method further comprises administration of at least one MetAP2 inhibitor or a pharmaceutically acceptable salt thereof.
[00268] Embodiment 7. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is castration-resistant prostate cancer.
[00269] Embodiment 8. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is castration-sensitive prostate cancer. [00270] Embodiment 9a. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is PTEN-deficient prostate cancer or partially PTEN-deficient prostate cancer.
[00271] Embodiment 9b. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is PTEN-altered prostate cancer or partially PTEN-altered prostate cancer.
[00272] Embodiment 10. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is aggressive variant prostate cancer (AVPC).
[00273] Embodiment 11. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is neuroendocrine prostate cancer (NEPC).
[00274] Embodiment 12. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the at least one MetAP2 inhibitor, or pharmaceutically acceptable salt thereof, and the enzalutamide, or pharmaceutically acceptable salt thereof, are administered concurrently or in temporal proximity.
[00275] Embodiment 13. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one androgen deprivation therapy.
[00276] Embodiment 14. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has undergone an orchiectomy.
[00277] Embodiment 15. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 14, wherein the orchiectomy is a subcapsular orchiectomy.
[00278] Embodiment 16. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one luteinizing hormone-releasing hormone (LHRH) agonist.
[00279] Embodiment 17. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 16, wherein the at least one luteinizing hormone-releasing hormone (LHRH) agonist is selected from leuprolide, goserelin, triptorelin and histrelin.
[00280] Embodiment 18. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one LHRH antagonist. [00281] Embodiment 19. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 18, wherein the at least one LHRH antagonist is selected from degarelix and relugolix.
[00282] Embodiment 20. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has been previously administered at least one androgen receptor antagonist.
[00283] Embodiment 21. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 20, wherein the androgen receptor antagonist is selected from flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide.
[00284] Embodiment 22. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 21, wherein the androgen receptor antagonist is enzalutamide.
[00285] Embodiment 23. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is resistant to treatment with androgen deprivation therapy.
[00286] Embodiment 24. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 23, wherein the androgen deprivation therapy comprises performing an orchiectomy, administering at least one luteinizing hormone-releasing hormone (LHRH) agonist, administering at least one LHRH antagonist, administering at least one estrogen, or any combination thereof.
[00287] Embodiment 25. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 24, wherein the orchiectomy is a subcapsular orchiectomy.
[00288] Embodiment 26. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 24, wherein the at least one luteinizing hormone-releasing hormone (LHRH) agonist is selected from leuprolide, goserelin, triptorelin and histrelin.
[00289] Embodiment 27. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 24, wherein the at least one LHRH antagonist is selected from degarelix and relugolix.
[00290] Embodiment 28. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the prostate cancer is resistant to treatment with an androgen receptor antagonist.
[00291] Embodiment 29. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 28, wherein the androgen receptor antagonist is selected from flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide. [00292] Embodiment 30. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is administered/for administration within one day, two days, three days, four days, five days, six days or one week of the subject exhibiting PSA nadir.
[00293] Embodiment 31. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is administered/for administration about two weeks, or about three weeks, or about four weeks, or about five weeks after the subject has exhibited PSA nadir, and wherein the PSA level in the subject has increased from PSA nadir.
[00294] Embodiment 32. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the subject has at least one metabolic dysfunction, wherein the metabolic dysfunction is selected from visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated 14b Ale, or any combination thereof.
[00295] Embodiment 33. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the metabolic dysfunction is a treatment-induced metabolic dysfunction.
[00296] Embodiment 34. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is selected from:
Figure imgf000047_0001
pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3: 1, preferably wherein the ratio of x to y is about 11 : 1. [00297] Embodiment 31. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is:
Figure imgf000048_0001
(Compound 1), or a pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30: 1 to about 3: 1, preferably wherein the ratio of x to y is about 11 : 1.
[00298] Embodiment 35. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, or pharmaceutically acceptable salt thereof, wherein the MetAP2 inhibitor is administered/for administration to the subject in an amount of: i) about 27 mg/m2; ii) about 36 mg/m2; iii) about 49 mg/m2; or iv) about 65 mg/m2.
[00299] Embodiment 36. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the MetAP2 inhibitor is administered/for administration: i) once every 7 days (Q7D); ii) once every 14 days (Q14D); or iii) once every 21 days (Q21D).
[00300] Embodiment 37. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, or pharmaceutically acceptable salt thereof, wherein the enzalutamide is administered/for administration to the subject in an amount of: i) about 40 mg; ii) about 80 mg; iii) about 120 mg; or iv) about 160 mg.
[00301] Embodiment 38. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein the enzalutamide is administered/for administration daily.
[00302] Embodiment 39. The method, MetAP2 inhibitor, combination, or enzalutamide of any one of the preceding embodiments, wherein administration of the at least one MetAP2 inhibitor results in a reduction in the size of the prostate cancer.
[00303] Embodiment 40. The method, MetAP2 inhibitor, combination, or enzalutamide of embodiment 36, wherein the reduction in the size of the prostate cancer is at least about a 10%, or about a 20%, or about a 30%, or about a 40%, or about a 50%, or about a 60%, or about a 70%, or about an 80%, or about a 90%, or about a 99% reduction in tumor volume.
[00304] Example 1
[00305] The following is a non-limiting example of the treatment of castration-sensitive prostate cancer using Compound 1 of the present disclosure.
[00306JNSG mice were injected subcutaneously with 2xl06 LNCaP cells. When tumors reached approximately 200 mm3, the mice were split into two treatment groups of four mice each. The first treatment group received Compound 1 in an amount of 12 mg/kg, administered subcutaneously once every 4 days. The second treatment group received a negative control, vehicle treatment comprising 5% mannitol in water.
[00307] FIG. 1 shows the tumor volume in individual mice (left panel) and the average tumor volume across all mice (right panel) in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment.
[00308] FIG. 2 shows the average PSA levels of mice (left panel) and the endpoint tumor mass (right panel) in the Compound 1 and Vehicle control treatment groups.
[00309] As shown in FIGs. 1 and 2, treatment with Compound 1 resulted in both a decrease in tumor volume as well as a decrease in PSA levels. [00310] FIG. 3 shows the body weight of individual mice (left panel) and the average body weight across all mice (right panel) in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment.
[00311] FIG. 4 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
[00312] FIG. 5 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
[00313] Without wishing to be bound by theory, the results presented in FIGs. 3-5 demonstrate that treatment with Compound 1 was well-tolerated.
[00314] FIG. 6 is a graph showing the overall survival of the mice in the Compound 1 and Vehicle control treatment groups. As shown in FIG. 6, treatment with Compound 1 resulted in increased survival of the mice.
[00315] FIG. 7 shows necropsy images of tumors excised from mice in the Compound 1 and Vehicle control treatment groups.
[00316] FIG. 8 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 and Vehicle control treatment groups. As would be appreciated by the skilled artisan, the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 8, treatment with Compound 1 results in a decrease in tumor vasculature as compared to treatment with the vehicle control.
[00317] Without wishing to be bound by theory, the results presented in this example demonstrate that Compound 1 of the present disclosure can be used to treat castrationsensitive prostate cancer.
[00318] Example 2
[00319] The following is a non-limiting example of the prevention of castration-resistant prostate cancer development using Compound 1 of the present disclosure.
[00320]NSG mice were injected subcutaneously with 2xl06 LNCaP cells. When tumors reached approximately 200 mm3, the mice were physically castrated and subsequently enrolled in one of three treatment groups within 5 to 8 days. The first treatment group received Compound 1 in an amount of 6 mg/kg, administered subcutaneously once every 4 days. The second treatment group received Compound 1 in an amount of 12 mg/kg administered subcutaneously once every 4 days. The third treatment group received a negative control, vehicle treatment comprising 5% 5% mannitol in water. [00321] FIG. 9 shows the average tumor volume across all mice in the three treatment groups. The vertical dashed lines denote the start of treatment and the gray box denotes castration. FIG. 10 shows the tumor mass at the conclusion of the study. The results shown in FIGs. 9 and 10 demonstrate that the administration of Compound 1 prevented tumor growth and resulted in smaller tumors at the end of the study.
[00322] FIG. 11 shows the average PSA levels across all mice in the three treatment groups during the course of the study. The results shown in FIG. 11 demonstrate that PSA levels were not affected by treatment with Compound 1.
[00323] FIG. 12 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups. FIG. 13 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups. FIG. 14 shows average body weight across all mice in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment. In FIGs. 12-14, the Compound 1 6 mg/kg treatment group is denoted as “Cpdl (6 mpk)” and the Compound 1 12 mg/kg treatment group is denoted as “Cpdl (12 mpk)”.
[00324] Without wishing to be bound by theory, the results presented in FIGs. 12-14 demonstrate that treatment with Compound 1 was well-tolerated.
[00325] FIG. 15 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the three treatment groups. As would be appreciated by the skilled artisan, the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 15, treatment with Compound 1 prevented the formation of tumor vasculature as compared to treatment with the vehicle control.
[00326] Without wishing to be bound by theory, the results presented in this example demonstrate that Compound 1 of the present disclosure can be used to prevent castrationresistant prostate cancer.
[00327] Example 3
[00328] The following is a non-limiting example of the treatment of castration-resistant prostate cancer using Compound 1 of the present disclosure.
[00329] NSG mice prepared as described in Example 2 were subsequently enrolled in one of two treatment groups 2-4 weeks after castration and the recurrence of high PSA levels and tumor growth (i.e., castration-resistant prostate cancer). The first treatment group received Compound 1 in an amount of 12 mg/kg, administered subcutaneously once every 4 days. The second treatment group received a negative control, vehicle treatment comprising 5% mannitol in water(denoted in some figures as “Veh”).
[00330] FIG. 16 shows the tumor volume in individual mice (top panel) and the average tumor volume across all mice (bottom panel) in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment. FIG. 17 shows the endpoint tumor mass (left panel) and average PSA levels of mice (right panel) and in the Compound 1 and Vehicle control treatment groups. As shown in FIGs. 16 and 17, treatment with Compound 1 resulted a decrease in tumor volume while PSA levels were not affected.
[00331] FIG. 18 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment.
[00332] FIG. 19 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
[00333] FIG. 20 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the Compound 1 and Vehicle control treatment groups.
[00334] Without wishing to be bound by theory, the results presented in FIGs. 18-20 demonstrate that treatment with Compound 1 was well-tolerated.
[00335] FIG. 21 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 and Vehicle control treatment groups. As would be appreciated by the skilled artisan, the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 21, treatment with Compound 1 results in a decrease in tumor vasculature as compared to treatment with the vehicle control.
[00336] Without wishing to be bound by theory, the results presented in this example demonstrate that Compound 1 of the present disclosure can be used to treat castrationresistant prostate cancer.
[00337] Example 4
[00338] The following is a non-limiting example of the treatment of established castrationresistant prostate cancer using Compound 1 of the present disclosure in combination with enzalutamide.
[00339] NSG mice prepared as described in Example 2, were subsequently enrolled in one of four treatment groups 2-4 weeks after castration and the recurrence of high PSA levels and tumor growth. The first treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with a negative control, vehicle treatment of 5% mannitol in water. The second treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with Compound 1 in an amount of 12 mg/kg, administered subcutaneously once every 4 days.
[00340] FIG. 22 shows the average tumor volume across mice in the first treatment group described above. The first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”). Dashed line denotes the start of treatment. [00341] FIG. 23 shows the average tumor volume across mice in the first and second treatment groups described above. The first treatment group was stratified into two groups - those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”). Dashed line denotes the start of treatment (enzalutamide or enzalutamide plus Compound 1).
[00342] FIG. 24 shows the endpoint tumor mass in the first and second treatment groups described above. The first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”).
[00343] FIG. 25 shows the PSA levels in the first and second treatment groups described above. The first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”). Dashed line denotes the start of treatment (enzalutamide or enzalutamide plus Compound 1).
[00344] As shown in FIGs. 22-25, treatment with Compound 1 in combination with enzalutamide resulted a decrease in tumor volume while PSA levels were not significantly affected.
[00345] FIG. 26 shows the body weight of individual mice (top panel) and the average body weight across all mice (bottom panel) in the first and second treatment groups described above. The vertical dashed lines denote the start of treatment.
[00346] FIG. 27 shows the liver, kidney, heart and lung weights at the endpoint of the study in select mice in the first and second treatment groups described above.
[00347] FIG. 28 shows the liver, kidney, heart and lung weights as a percentage of body weight at the endpoint of the study in select mice in the first and second treatment groups described above. [00348] Without wishing to be bound by theory, the results presented in FIGs. 26-28 demonstrate that treatment with Compound 1 in combination with enzalutamide is well- tolerated.
[00349] FIG. 29 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the first and second treatment groups described above. The first treatment group was stratified into two groups -those that responded to the treatment with enzalutamide alone (“responders”) and those that did not respond to enzalutamide alone (“non-responders”). As would be appreciated by the skilled artisan, the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 29, treatment with Compound 1 in combination with enzalutamide results in a decrease in tumor vasculature when compared to enzalutamide alone in the responder group.
[00350] Without wishing to be bound by theory, the results presented in this example demonstrate that Compound 1 of the present disclosure in combination with enzalutamide can be used to treat castration-resistant prostate cancer.
[00351] Example 5
[00352] The following is a non-limiting example of the treatment of castration-resistant prostate cancer using Compound 1 of the present disclosure.
[00353] Physically-castrated NSG mice were injected subcutaneously with patient derived castration-resistant prostate cancer tumor samples (LUCAP35CR). When tumors reached ~250mm3, mice were enrolled in one of two treatment groups. The first treatment group received Compound 1 in an amount of 8 mg/kg, administered subcutaneously once every 4 days. The second treatment group received a negative control, vehicle treatment comprising 5% mannitol in water.
[00354] FIG. 30 shows the average tumor volume across all mice in the Compound 1 and Vehicle control treatment groups. The vertical dashed lines denote the start of treatment. FIG. 31 shows the endpoint tumor mass in the Compound 1 and Vehicle control treatment groups. As shown in FIGs. 30 and 31, treatment with Compound 1 resulted in a decrease in tumor volume.
[00355] FIG. 32 shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 and Vehicle control treatment groups. As would be appreciated by the skilled artisan, the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 32, treatment with Compound 1 results in a decrease in tumor vasculature as compared to the vehicle control. [00356] Transcriptomic analysis of tumor samples from the first and second treatment groups was also performed.
[00357] FIG. 41 shows the expression levels of particular hypoxia induced, extracellular matrix-related genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00358] FIGs. 42A and 42B show the expression levels of particular glycolysis-related genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00359] FIG. 43 shows the expression levels of particular serine-glycine one-carbon (SOGC) pathway genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00360] FIG. 44 shows the expression levels of particular cholesterol uptake and synthesis pathway genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00361] FIG. 45 shows the expression levels of particular fatty acid synthesis pathway genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle). [00362] FIG. 46 shows the expression levels of particular cell cycle genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00363] FIG. 47 shows the expression levels of particular hormone/cytokine receptor genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00364] FIG. 48 shows the expression levels of particular kinase genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00365] FIG. 49 shows the expression levels of particular transcription factor genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00366] FIG. 50 shows the expression levels of particular tumor-inhibiting genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00367] FIGs. 51 A and 5 IB show the expression levels of particular tumor-growth promoting/survival genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00368] FIG. 52 shows the expression levels of particular nucleotide synthesis genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00369] FIG. 53 shows the expression levels of particular lipid metabolism genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle).
[00370] FIG. 54 shows the expression levels of particular immune recognition genes in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle). [00371] FIG. 55 shows the expression levels of particular immune recognition genes, specifically CD74 ligands and binding partners, in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle). As would be appreciated by the skilled artisan, studies have implicated MIF in tumor development and cancer progression and that MIF signaling via CD74 requires an additional co-receptor such as CXCR4 or CD44.
[00372] FIG. 56 shows the expression levels of particular genes encoding regulators of MHC II, in tumor samples from treatment group 1 (Compound 1) and treatment group 2 (vehicle). AS would be appreciated by the skilled artisan, proper stimulation of T cells requires efficient HLA class II antigen presentation by professional or non-professional antigen-presenting cells, including prostate cancer cells. Moreover, the transcription factor CIITA, whose expression is decreased in many cancers, positively regulates the expression of MHC II genes. Finally, the enzyme GILT, down-regulated in many cancers including prostate cancer, facilitates processing of MHC II-antigen complexes prior to their display on the cell surface. [00373] In addition to the transcriptomic analysis shown in FIGs. 41-56, the bulk RNASeq data obtained from tumor samples from the first and second treatment groups was analyzed for changes in mouse genes, removing signals from human genes. As would be appreciated by the skilled artisan, such an analysis allows for interrogation of the tumor microenvironment (TME). Results from this analysis are shown in Table C.
[00374] Table C
Figure imgf000056_0001
[00375] As shown in Table C, the TME in mice treated with Compound 1 was les fibrotic, based on the reduction in multiple collagen genes, and less immunosuppressive, based on the reduction in the expression of Argl. Moreover, without wishing to be bound by theory, the increased expression of multiple genes involved in adipocyte function indicate increased adipocyte differentiation or hypertrophy, with increased adiponectin potentially exhibiting anti-tumor effects.
[00376] Without wishing to be bound by theory, the results presented in this example demonstrate that Compound 1 of the present disclosure can be used to treat castrationresistant prostate cancer.
[00377] Example 6
[00378] Gene expression analysis was performed for various treatment groups presented in Examples 1-5 above.
[00379] The left panel in FIG. 35 shows a chart of the number of differentially expressed human genes for each pairwise comparison of treatment groups (see Table A for details on comparison groups). Differential gene expression (DE) is defined by abs.FC > 1.5 and FDR pvalue < 0.05. The right panel in FIG. 35 shows bubble plots of a selection of significantly enriched (adj .pvalue < 0.05) cellular pathways from the MSigDB (Molecular Signatures Database) for each of the comparisons presented in Table A and the left panel of FIG. 35.
[00380] Table A
Figure imgf000057_0001
[00381] FIGs. 36-40 show bubble plots of genes of interest including LINGO4, SORCS2, KCND3, SNRNP48, GLS, BAG1, AR, KLK3, DDC, STEAP4, FKBP5, FOLH1, PPIA, RAB37, TXN, SH3BGRL, GAPDH, METAP2, R0R2, CTHRC1, DVL3, ARRB2, PPARG, WNT5A, MAPK10, PPKCZ, DVL2, AMACR, PCGEM1, PC A3, PSCA, NIKX3-1, AZGP1, H0XB13, SOX9 and RLN1 for pairwise comparisons of treatment groups (see Table B for details on comparison groups). The shading indicates the direction of differential expression (e.g. up or down) and the size indicates the significance at FDR.p<=0.05.
[00382] Table B
Figure imgf000057_0002
Figure imgf000058_0001
[00383] Example 7
[00384] The following is a non-limiting example of the treatment of enzalutamide-resistant, castration-resistant prostate cancer using Compound 1 of the present disclosure.
[00385]LUCaP.35CR PDX patient-derived castrate resistant prostate cancer tumors were transplanted into castrated NSG mice. When tumors reached approximately 100-200 mm3 and PSA was approximately 30-50ng/ml, the mice were treated with enzalutamide in an amount of 10 mg/kg daily by oral gavage. Treatment continued for approximately 2-3 weeks until tumor size increased to 400-500 mm3 demonstrating that treatment of the tumors with enzalutamide was ineffective (i.e. the tumors were enzalutamide-resistant). The mice were then enrolled in two treatment groups. The first treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with a negative control, vehicle treatment of 5% mannitol in water. The second treatment group received enzalutamide in an amount of 10 mg/kg daily by oral gavage in combination with Compound 1 in an amount of 8 mg/kg, administered subcutaneously once every 4 days.
[00386] FIG. 33 A shows the average tumor volume across all mice in the two treatment groups The gray box denotes the time period of enzalutamide treatment and the vertical dashed lines denotes the start of resistance to the enzalutamide treatment and start of treatment with Compound 1. FIG. 33B shows the endpoint tumor mass in the first and second treatment groups described above. The results shown in FIGs. 33A and 33B demonstrate that the administration of Compound 1 in combination with enzalutamide prevented tumor growth and resulted in smaller tumors at the end of the study compared to tumors in mice treated with enzalutamide alone.
[00387] FIG. 33C shows immunohistochemistry analysis of CD34 immunoreactivity from select mice in the Compound 1 plus enzalutamide and Vehicle enzalutamide control treatment groups described above. As would be appreciated by the skilled artisan, the endothelial marker CD34 can be used to quantify tumor vasculature. Accordingly, as shown in FIG. 33C, treatment with Compound 1 results in a decrease in tumor vasculature as compared to the vehicle control.
[00388] Without wishing to be bound by theory, the results presented in this example demonstrate that Compound 1 of the present disclosure can be used to treat enzalutamide- resistant, castration-resistant prostate cancer.
[00389] Example 8
[00390] The following is a non-limiting example of the treatment of aggressive variant prostate cancer (AVPC), including neuroendocrine prostate cancer (NEPC) using Compound 1 of the present disclosure.
[00391] LTL545 PDX patient-derived AVPC tumor xenografts (specifically NEPC tumor xenografts) were transplanted into NSG mice. When tumors reached approximately 200 mm3, the mice were enrolled in one of two treatments. The first treatment group received Compound 1 in an amount of 8 mg/kg, administered subcutaneously once every 4 days. The second treatment received a negative control, vehicle treatment comprising 5% mannitol in water.
[00392] FIG. 34A shows the tumor volume of all mice in the two treatment groups and FIG. 34B shows the average tumor volume across all mice in the two treatment groups. The vertical dashed lines denotes the onset of treatment with Compound 1. FIG. 34C shows the endpoint tumor mass in the first and second treatment groups described above. The results shown in FIGs. 34A, 34B and 34C demonstrate that the administration of Compound 1 attenuated AVPC tumor growth and resulted in smaller AVPC tumors at the end of the study. [00393] Without wishing to be bound by theory, the results presented in this example demonstrate that Compound 1 of the present disclosure can be used to treat AVPC, including NEPC.

Claims

What is claimed is:
1. A method of treating prostate cancer in a subject, the method comprising administering at least one amount of at least one MetAP2 inhibitor to the subject, wherein the MetAP2 inhibitor is:
Figure imgf000060_0001
(Compound 1), or a pharmaceutically acceptable salt thereof, wherein x is in the range of 1 to about 450, y is in the range of 1 to about 30 and n is in the range of 1 to about 100, preferably wherein the ratio of x to y is in the range of about 30:1 to about 3: 1, preferably wherein the ratio of x to y is about 11 : 1, wherein the subject has been previously administered at least one prostate cancer treatment, wherein the prostate cancer treatment comprises androgen deprivation therapy (ADT) and/or at least one androgen receptor antagonist, wherein the prostate cancer has become resistant to treatment with the androgen deprivation therapy (ADT) and/or at least one androgen receptor antagonist, wherein administration of the MetAP2 inhibitor results in reduction in size of the prostate cancer.
2. The method of claim 1, wherein the method further comprises administering to the subject at least one amount of enzalutamide.
3. The method of claim 1 or claim 2, wherein the prostate cancer is castration-resistant prostate cancer.
4. The method of claim 1 or claim 2, wherein the prostate cancer is castration-sensitive prostate cancer.
5. The method of any one of the preceding claims, wherein the prostate cancer is PTEN- deficient prostate cancer or partially PTEN-deficient prostate cancer.
6. The method of any one of the preceding claims, wherein the prostate cancer is aggressive variant prostate cancer (AVPC).
7. The method of any one of the preceding claims, wherein the prostate cancer is neuroendocrine prostate cancer.
8. The method of any one of the preceding claims, wherein the androgen deprivation therapy comprises performing an orchiectomy, administering at least one luteinizing hormone-releasing hormone (LHRH) agonist, administering at least one LHRH antagonist, administering at least one estrogen, or any combination thereof.
9. The method of claim 8, wherein the orchiectomy is a subcapsular orchiectomy.
10. The method of claim 8, wherein the at least one LHRH agonist is selected from leuprolide, goserelin, triptorelin and histrelin.
11. The method of claim 8, wherein the at least one LHRH antagonist is selected from degarelix and relugolix.
12. The method of any one of the preceding claims, wherein the at least one androgen receptor antagonist is selected from flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, and darolutamide, preferably wherein the at least one androgen receptor antagonist is enzalutamide.
13. The method of any one of the preceding claims, wherein the MetAP2 inhibitor is administered within one day, two days, three days, four days, five days, six days or one week of the subject exhibiting PSA nadir.
14. The method of any one of the preceding claims, wherein the MetAP2 inhibitor is administered about two weeks, or about three weeks, or about four weeks, or about five weeks after the subject has exhibited PSA nadir, and wherein the PSA level in the subject has increased from PSA nadir.
15. The method of any one of the preceding claims, wherein the subject has at least one metabolic dysfunction, wherein the metabolic dysfunction is selected from visceral adiposity, dyslipidemia, obesity (BMI >30), elevated leptin levels, depressed adiponectin levels, high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, hyperleptinaemia, high fasting glucose, elevated HbAlc, or any combination thereof.
16. The method of any one of the preceding claims, wherein the metabolic dysfunction is a treatment-induced metabolic dysfunction.
17. The method of any one of the preceding claims, wherein the MetAP2 inhibitor is administered to the subject in an amount of: i) about 27 mg/m2; ii) about 36 mg/m2; iii) about 49 mg/m2; or iv) about 65 mg/m2.
18. The method of any one of the preceding claims, wherein the MetAP2 inhibitor is administered: i) once every 7 days (Q7D); ii) once every 14 days (Q14D); or iii) once every 21 days (Q21D).
19. The method of any one of the preceding claims, wherein the enzalutamide is administered/for administration to the subject in an amount of: i) about 40 mg; ii) about 80 mg; iii) about 120 mg; or iv) about 160 mg.
20. The method of any one of the preceding claims, wherein the enzalutamide is administered daily.
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