Biomarkers and applications of METAP2 inhibitors

Abstract

The present disclosure relates to small molecule or polymer-conjugated MetAP2 inhibitors. The present disclosure also relates to methods for treating a metabolic dysfunction associated with a disease (e.g., cancer) or alleviating at least one symptom of a metabolic dysfunction associated with a disease (e.g., cancer). The present disclosure also relates to methods for treating cancer or alleviating at least one symptom of cancer, comprising administering a combination of a polymer-conjugated MetAP2 inhibitor and at least one second agent, wherein the second agent can induce metabolic dysfunction.

Description

[0001] Related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 751,335, filed on October 26, 2018, and U.S. Provisional Application No. 62 / 844,271, filed on May 7, 2019. The contents of each of the foregoing patent applications are hereby incorporated by reference in their entirety. Background of the Invention

[0004] Obesity and metabolic dysfunction are common disease states in populations worldwide. This chronic disease state leads to systemic inflammation, is pro-angiogenic, pro-fibrotic, and, in many patients, produces an immunosuppressive state, which complicates the treatment of other comorbidities such as cancer. While obesity is a growing problem, the aging population further complicates treatment, as this patient population with multiple comorbidities requires both methods to identify which obesity-related factors adversely affect other diseases and methods to provide therapies that can slow the progression or reverse these factors.

[0005] Conventional chemotherapy and targeted therapies have been shown to be less effective in obese cancer patients (Incio et al., Cancer Discov; (2016) 6(8); 852–69, Kruger et al., British Journal of Cancer (2018) 119:832–839). Recently, a new class of cancer treatments has emerged, immunotherapy, which has shown clinical benefit in a significant percentage of cancer patients. However, and quite unexpectedly, the majority of cancer patients still show resistance to immunotherapy treatment (Yu & Cui, 2018, Oncol. Lett. 16: 4105-41130). It is becoming increasingly clear that cancer patients with obesity and / or metabolic dysfunction fail to respond to treatment (including traditional chemotherapy and emerging therapies such as immunotherapy) in the same way as their non-obese counterparts (Murphy et al., J Immunol 2018;201:1837-1841). A major challenge lies in identifying which obesity-related factor(s) are the key contributors to this unexpected treatment resistance and reversing these factors.

[0006] Certain targeted therapies for cancer and other diseases lose their efficacy after a relatively short period of time. Recently, one mechanism explaining this loss of activity is "induced metabolic dysfunction"—including hyperglycemia leading to hyperinsulinemia—either by the treatment itself or by co-administered agents. Here, we show that treatment with the disclosed compounds ameliorate the induced metabolic dysfunction, enabling sustained treatment with the therapeutic agent.

[0007] Cancer therapies can induce metabolic dysfunction, potentially limiting their efficacy. Hyperglycemia during chemotherapy occurs in approximately 10% to 30% of patients. Glucocorticoids and L-asparaginase are well known to cause acute hyperglycemia during chemotherapy. Prolonged hyperglycemia is also commonly observed, particularly in patients with hematologic malignancies treated with L-asparaginase-based regimens and total body irradiation. Glucocorticoid-induced hyperglycemia often develops due to increased insulin resistance, decreased insulin secretion, and excessive hepatic glucose output, depending on the type, dose, and delivery of the glucocorticoid formulation. The incidence of hyperglycemia (defined as a blood glucose >200 mg / dL) is >50% in hospitalized patients treated with glucocorticoids but without a known history of diabetes. Mammalian target of rapamycin (mTOR) inhibitors are associated with a high incidence of hyperglycemia (ranging from 13% to 50%). Immunotherapy induces hyperglycemia in patients treated with pembrolizumab, with hyperglycemic events reported in 45% to 49% of patients, and 3% to 6% of patients experiencing grade 3 or 4 hyperglycemia (Hwangbo et al. Endocrinol Metab (Seoul) 2017 Mar;32(1):23–29).

[0008] Cancer cells derive the majority of their energy from glucose. To meet their increased glucose demand, the PI3K / AKT / mTOR pathway is often upregulated (amplified) or mutated. Concerted efforts have been made to develop therapies that inhibit or downregulate this pathway. However, inhibition of this pathway leads to on-target toxicities that hinder efficacy by creating a hyperglycemia / hyperinsulinemia feedback loop, which can lead to treatment failure.

[0009] Obesity increases circulating estrogen, insulin, and IGF, and induces chronic low-grade inflammation. These diverse effects converge, directly or indirectly, to induce well-established tumor pathways and contribute to the accumulation of myeloid-derived suppressor cells, while simultaneously reprogramming macrophages to an alternately activated proinflammatory and immunosuppressive M2 phenotype. Among the many pathways affected by obesity are the proangiogenic factors VEGF, bFGF, IGF, and PLGF (Silha et al., International Journal of Obesity (2005) 29, 1308–1314), as well as key transcription factors including STAT3 (Wunderlich et al., (2013) Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity, JAK-STAT, 2:2, e23878), plus multiple immunosuppressive factors, including myeloid-derived suppressor cells (MDSCs) (Ostrand-Rosenberg (2018) Myeloid-derived-suppressor cells their role in cancer and obesity Current Opinion in Immunology 51:68-75). MDSCs and M2 macrophages are the main source of immunosuppression, which allows tumors to escape from effective host immune surveillance and resist anticancer therapy (Weber et al. Front. Immunol. 9:1310.doi: 10.3389 / fimmu.2018.01310). The induction and preferential shift of macrophages toward an immunosuppressive M2 phenotype may be a primary physiological and metabolic adaptive response to insulin insensitivity and a secondary consequence of immune processes in the context of chronic low-grade inflammation. These processes can be modulated by tumor cells to promote angiogenesis, tumor cell motility and invasion, and metastasis, leading to poor therapeutic outcomes (Okwan-Duodu et al., 2013).

[0010] Many proteins have been identified that are responsible for limiting the clinical benefit of immunotherapy treatment. These include the enzymes indoleamine-pyrrole 2,3-dioxygenase (IDO-1) and arginase-1 (Arg-1), the cytokine IL-10, and the adipokine leptin. Furthermore, tumor infiltration by regulatory T cells (Tregs), alternatively polarized (“M2”) macrophages, and myeloid-derived suppressor cells (MDSCs) has been associated with tumor escape from immune surveillance and subsequent disease progression (Shimizu et al., International Immunology , 30(10): 445–455).

[0011] MetAP2 inhibitors have a long clinical history of demonstrating antitumor and antimetabolite effects in animal studies as well as in human clinical trials (Tran et al. Cancer Chemother. Pharmacol. (2004) 54: 308–314; Joharapurkar et al. Diabetes, Metabolic Syn. and Obesity: Targets and Therapy , (2014), 7:73–84). Here, we show that administration of a MetAP2 inhibitor can suppress or reverse the expression or amount of some of these biomarkers, which is expected to lead to improved clinical benefits for obese and potentially cancer patients with metabolic dysfunction.

[0012] Recent work has also shown that the adipokine leptin acts as a contributor to tumor growth in a mouse model of obesity-accelerated breast cancer (Strong et al., Breast Cancer Research (2015) 17:112-27) and as a mediator of obesity-associated resistance to immunotherapy in a different mouse model of obesity-accelerated renal cancer (Murphy et al., J. Immunol., 2018;201:1837-41). One mechanism by which leptin promotes obesity-accelerated cancer is by increasing the abundance of MDSCs (Clements et al., J Leukoc Biol . 2018;103:395–407). SUMMARY OF THE INVENTION

[0014] The present disclosure provides methods for modifying the expression of cells, tissues, and / or proteins that would otherwise hinder clinical activity of various cancer treatments.In certain aspects, the subject is overweight, obese, or has a metabolic dysfunction.

[0015] The present disclosure provides a method of treating cancer or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering a therapeutically effective amount of at least one of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a therapeutically effective amount of at least one second active agent, wherein the at least one compound and the at least one second active agent are administered in an amount sufficient to treat cancer or alleviate at least one symptom of cancer.

[0016] The present disclosure provides a combination product comprising at least one of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and at least one second active agent for use in a method of treating cancer or alleviating at least one symptom of cancer in a subject, wherein the at least one compound and the at least one second active agent are administered to the subject in an amount sufficient to treat the cancer or alleviate at least one symptom of cancer.

[0017] The present disclosure provides a method for reducing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, growth factors, or any combination thereof in a tumor, in a tumor microenvironment, in plasma, or in any combination thereof in a subject, comprising administering a therapeutically effective amount of at least one of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a therapeutically effective amount of at least one second active agent, wherein the at least one compound and the at least one second active agent are administered in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof.

[0018] The present disclosure provides a combination product comprising at least one of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and at least one second active agent for use in reducing IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4 in a subject having cancer. , growth factors, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof, wherein the at least one compound and the at least one second active agent are administered to a subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, growth factors, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof.

[0019] The present disclosure provides a method for treating cancer or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound represented by the formula: ZQXYC(O)-W, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof: ZQXYC(O)-W, wherein, independently for each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, spermine, urea, thiazolinone ... AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q)r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6, in combination with a therapeutically effective amount of at least one second active agent, wherein the at least one compound and the at least one second active agent are administered in an amount sufficient to treat cancer or alleviate at least one symptom of cancer.

[0020] The present disclosure provides a combination product comprising at least one compound represented by the following formula, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof: ZQXYC(O)-W, wherein, independently for each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, chromatin, threonine, valine, threonine ... AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5 or 6, and at least one second active agent, for use in a method of treating cancer or alleviating at least one symptom of cancer in a subject, wherein the at least one compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and the at least one second active agent are used to be administered to the subject in an amount sufficient to treat the cancer or alleviate at least one symptom of cancer.

[0021] The present disclosure provides a method for reducing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, growth factors, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof in a subject, comprising administering a therapeutically effective amount of at least one compound represented by the following formula: ZQXYC(O)-W, wherein, independently for each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6, in combination with a therapeutically effective amount of at least one second active agent, wherein the at least one compound and the at least one second active agent are administered in an amount sufficient to reduce at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof.

[0022] The present disclosure provides a combination product comprising at least one compound represented by the following formula, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof: ZQXYC(O)-W, wherein, independently for each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, chromatin, threonine, valine, threonine ... AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5 or 6, and at least one second active agent, for use in a method of reducing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, growth factors, or any combination thereof in a tumor, in a tumor microenvironment, in plasma, or in any combination thereof in a subject having cancer, wherein the at least one compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and the at least one second active agent are administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, growth factors, or any combination thereof.

[0023] The present disclosure provides a method of treating cancer or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering a therapeutically effective amount of at least one of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, wherein the compound is administered in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof.

[0024] The present disclosure provides at least one formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, for treating cancer or alleviating at least one symptom of cancer in a subject, wherein the at least one compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, is administered to the subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof.

[0025] The present disclosure provides a method for treating or alleviating at least one symptom of a treatment-related metabolic dysfunction in a subject suffering from cancer, comprising administering a therapeutically effective amount of at least one of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, wherein the compound is administered in an amount sufficient to treat a metabolic dysfunction associated with the treatment or alleviate at least one symptom of a metabolic dysfunction associated with the treatment in a subject suffering from cancer.

[0026] The present disclosure provides at least one formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, for treating a metabolic dysfunction associated with treatment or alleviating at least one symptom of a metabolic dysfunction associated with treatment in a subject suffering from cancer, wherein the at least one compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, is administered to the subject in an amount sufficient to treat the metabolic dysfunction associated with treatment or alleviating at least one symptom of a metabolic dysfunction associated with treatment.

[0027] The present disclosure provides a method for reducing the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, growth factors, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof in a subject having cancer, comprising administering a therapeutically effective amount of at least one of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, wherein the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof in a tumor, in the tumor microenvironment, in plasma, or in any combination thereof is reduced.

[0028] The present disclosure provides at least one formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5 or 6; or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof for use in reducing IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, growth factors, or any combination thereof in a subject having cancer The method of claim 1, wherein the at least one compound, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, is administered to a subject in an amount sufficient to reduce the amount of at least one of IL-10, arginase-1, myeloid-derived suppressor cells, regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, a growth factor, or any combination thereof, in a tumor, in the tumor microenvironment, in plasma, or any combination thereof.

[0029] The present disclosure provides methods for treating cancer or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one PI3K inhibitor. The present disclosure also provides combination products comprising at least one MetAP2 inhibitor and at least one PI3K inhibitor for use in treating cancer or alleviating at least one symptom of cancer in a subject. The present disclosure also provides combination products comprising at least one MetAP2 inhibitor and at least one PI3K inhibitor for use in the manufacture of a medicament for treating cancer or alleviating at least one symptom of cancer in a subject.

[0030] The present disclosure provides methods for treating cancer or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one AKT inhibitor. The present disclosure also provides combination products comprising at least one MetAP2 inhibitor and at least one AKT inhibitor for use in treating cancer or alleviating at least one symptom of cancer in a subject. The present disclosure also provides combination products comprising at least one MetAP2 inhibitor and at least one AKT inhibitor for use in the manufacture of a medicament for treating cancer or alleviating at least one symptom of cancer in a subject.

[0031] The present disclosure provides methods for treating cancer or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one mTOR inhibitor. The present disclosure also provides combination products comprising at least one MetAP2 inhibitor and at least one mTOR inhibitor for use in treating cancer or alleviating at least one symptom of cancer in a subject. The present disclosure also provides combination products comprising at least one MetAP2 inhibitor and at least one mTOR inhibitor for use in the manufacture of a medicament for treating cancer or alleviating at least one symptom of cancer in a subject.

[0032] The present disclosure provides a method for treating cancer therapy-induced metabolic dysfunction or alleviating at least one symptom of cancer therapy-induced metabolic dysfunction in a subject, comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor. The present disclosure provides at least one MetAP2 inhibitor for treating cancer therapy-induced metabolic dysfunction or alleviating at least one symptom of cancer therapy-induced metabolic dysfunction in a subject. Cancer treatment may comprise administering a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, or a PI3K / AKT / mTOR pathway inhibitor, or any combination thereof.

[0033] In some aspects of the foregoing methods, combination products, and uses, the at least one MetAP2 inhibitor can be any conjugate or compound of the disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative of any conjugate or compound of the disclosure. In some aspects, the at least one MetAP2 inhibitor can be a conjugate or compound of the formula: .

[0034] In some aspects of the foregoing methods, combination products, and uses, the at least one MetAP2 inhibitor can be ZGN-1061 or Beloranib.

[0035] In some aspects of the foregoing methods, combinations and uses, the at least one compound or the at least one MetAP2 inhibitor can be of the formula wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) mCO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6. In some aspects, Z can be represented by a formula selected from the group consisting of:

[0036]

[0037]

[0038]

[0039]

[0040] .

[0041] In some aspects, R4 can be methyl. In some aspects, R5 can be methyl. In some aspects, R6 can be 2-hydroxypropyl. In some aspects, Z can be –NH-AA6-C(O)-QXYC(O)-W. In some aspects, AA6 can be glycine. In some aspects, Z can be –NH-AA5-AA6-C(O)-QXYC(O)-W. In some aspects, AA5 can be leucine and AA6 can be glycine. In some aspects, AA5 can be valine and AA6 can be glycine. In some aspects, AA5 can be phenylalanine and AA6 can be glycine. In some aspects, AA5 can be glycine and AA6 can be glycine. In some aspects, Z can be –NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In some aspects, AA5 can be leucine and each of AA3, AA4, or AA6 can be glycine. In some aspects, AA5 can be valine and each of AA3, AA4, or AA6 can be glycine. In some aspects, AA5 can be phenylalanine and each of AA3, AA4, or AA6 can be glycine. In some aspects, AA3 can be glycine, AA4 can be phenylalanine, AA5 can be leucine, and AA6 can be glycine. In some aspects, each of AA3, AA4, AA5, and AA6 can be glycine.

[0042] In some aspects, –QXY can be

[0043]

[0044] .

[0045] In some aspects, where W can be .

[0046] In some aspects, the ratio of x to y can be from about 30: 1 to about 3: 1. In some aspects, the ratio of x to y can be about 11:1.

[0047] In some aspects of the foregoing methods, combinations, and uses, the at least one MetAP2 inhibitor may have the formula

[0048]

[0049]

[0050] .

[0051] In some aspects of the foregoing methods, combinations, and uses, the at least one MetAP2 inhibitor can be represented by ZQXYC(O)-W, wherein, independently for each occurrence, Z is -H, -H2N-AA3-AA4-AA5-AA6-C(O)-, or Z is H2N-AA5-AA6-C(O); AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine. amino acids; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6.

[0052] In some aspects, Z can be -NH-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be leucine and AA6 can be glycine. In some aspects, Z can be -NH-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be valine and AA6 can be glycine. In some aspects, Z can be -NH-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be phenylalanine and AA6 can be glycine. In some aspects, Z can be -NH-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be glycine and AA6 can be glycine. In some aspects, Z can be -NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be leucine and each of AA3, AA4 or AA6 can be glycine. In some aspects, Z can be –NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be valine and each of AA3, AA4 or AA6 can be glycine. In some aspects, Z can be –NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be phenylalanine and each of AA3, AA4 or AA6 can be glycine. In some aspects, Z can be –NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, AA5 can be glycine, AA4 can be phenylalanine, AA5 can be leucine and AA6 can be glycine. In some aspects, Z can be –NH-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W, and each of AA3, AA4, AA5 and AA6 can be glycine. In some aspects, –QXY can be

[0053]

[0054] .

[0055] In some aspects, W can be .

[0056] In some aspects, the at least one MetAP2 inhibitor can be selected from:

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064] .

[0065] In some aspects of the foregoing methods, combinations, and uses, the at least one PI3K inhibitor can be Serabelisib (TAK-117), BYL-719, or any combination thereof. In some aspects of the foregoing methods, combinations, and uses, the AKT inhibitor can be AZD5363 (capivasertib).

[0066] In some aspects of the preceding methods, combination products, and uses, the therapeutically effective amount or effective amount of the at least one MetAP2 inhibitor can be from about 0.0001 mg / kg to about 5 mg / kg of body weight per day, or from about 0.001 to about 0.005 mg / kg of body weight per day, or from about 0.001 to about 0.1 mg / kg of body weight per day. In some aspects, the at least one MetAP2 inhibitor is administered from about 1 to about 5 times per week. In some aspects, the at least one MetAP2 inhibitor is administered on a q4d dosing schedule. In some aspects, the at least one MetAP2 inhibitor is administered on a q7d dosing schedule. In some aspects, the at least one MetAP2 inhibitor is administered on a q14d dosing schedule. In some aspects, the at least one MetAP2 inhibitor is administered once every three weeks. In some aspects, the at least one MetAP2 inhibitor is administered once monthly. In some aspects of the preceding methods, combination products, and uses, the subject is treated for at least about six months, or at least about one year, or at least two years, or at least three years. In some aspects of the foregoing methods, combinations, and uses, the at least one MetAP2 inhibitor can be administered parenterally or subcutaneously.

[0067] In some aspects of the previous methods, combination products, and uses, the therapeutically effective amount or effective amount of at least one compound of the present disclosure can be about 0.0001 mg / kg body weight to about 5 mg / kg body weight per day, or about 0.001 to about 0.005 mg / kg body weight per day, or about 0.001 to about 0.1 mg / kg body weight per day. In some aspects, at least one compound of the present disclosure is administered about 1 to about 5 times per week. In some aspects, at least one compound of the present disclosure is administered on a q4d dosing regimen. In some aspects, at least one compound of the present disclosure is administered on a q7d dosing regimen. In some aspects, at least one compound of the present disclosure is administered on a q14d dosing regimen. In some aspects, at least one compound of the present disclosure is administered once every three weeks. In some aspects, at least one compound of the present disclosure is administered once every month. In some aspects of the previous methods, combination products, and uses, the subject is treated for at least about six months, or at least about one year, or at least two years, or at least three years. In some aspects of the previous methods, combination products, and uses, at least one compound of the present disclosure can be administered parenterally or subcutaneously.

[0068] In some aspects of the foregoing methods, combination products, and uses, the cancer can be a metabolic hormone-sensitive cancer, postmenopausal HR+ / Her2- breast cancer, triple-negative breast cancer, prostate cancer, esophageal cancer, esophageal adenocarcinoma, tongue cancer, colorectal adenocarcinoma, gastrointestinal stromal tumor (GIST), cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, liver cancer, clear cell renal carcinoma, melanoma, multiple myeloma, thyroid cancer, insulin-like growth factor-sensitive lung cancer, or a combination thereof.

[0069] In some aspects of the foregoing methods, combination products, and uses, treating and / or alleviating at least one symptom of a metabolic dysfunction associated with the treatment may comprise reducing insulin levels, reducing hyperinsulinemia, reducing hyperglycemia, reducing C-peptide levels, increasing adiponectin, reducing leptin, reducing fasting insulin, improving insulin resistance, reducing the leptin / adiponectin ratio, reducing blood glucose levels, reducing cholesterol, reducing triglycerides, or a combination thereof in the subject. In some aspects of the foregoing methods, combination products, and uses, treating and / or alleviating at least one symptom of a metabolic dysfunction associated with the treatment may comprise preventing hyperglycemia induced by the treatment administration, preventing hyperinsulinemia induced by the treatment administration, and / or preventing elevated blood glucose levels induced by the treatment administration.

[0070] In some aspects of the foregoing methods, combinations, and uses, "reducing the level of" or "reducing the amount of" can mean reducing by at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%.

[0071] In some aspects of the foregoing methods, combination products, and uses, treatment, such as treatment associated with a metabolic dysfunction, can include administering a phosphoinositide 3-kinase (PI3K) inhibitor, an AKT inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor dexamethasone, or a combination thereof.

[0072] In some aspects of the foregoing methods, combinations, and uses, the second agent or second active agent may include a phosphoinositide 3-kinase (PI3K) inhibitor, an AKT inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor, dexamethasone, or a combination thereof.

[0073] PI3K inhibitors include, but are not limited to, serabelisib (TAK-117), BYL-719, or any other PI3K inhibitor known in the art. AKT inhibitors include, but are not limited to, AZD5363 (capavasertib), ipaseratib (GDC0068), and any other AKT inhibitor known in the art. MetAP2 inhibitors include, but are not limited to, ZGN-1061, Beloranib, and any other MetAP2 inhibitor known in the art. In some aspects, the MetAP2 inhibitor can be any conjugate or compound described herein.

[0074] PI3K / AKT / mTOR pathway inhibitors may include, but are not limited to (paclitaxel + sirolimus + tanspiramycin), (paclitaxel + sirolimus + tanspiramycin), A-443654, AB-610, ACP-2127, ADC-0008830, AE-116, AEZS-126, AEZS-127, afuresertib + trametinib, AL-58203, AL-58805, AL-58922, ALM-301, AP-185, AP-23675, AP-23841, apitolisib, ARQ-751, ASP-7486, AST-0669, AT-104, AT-13148, AUM-302, AZD-3147, AZD-8055, AZD-8154, BAY-1001931, BAY-1125976, BGT-226, bimiralisib, BN-107, BN-108, borussertib, buformin, BVD-723, capivasertib, CC-115, CC-2141, CC-2142, Certican ODT, CL-27, COTI-2, CT-365, NVP-BEZ235 p-toluenesulfonatetosylate), DC-120, DHM-25, dihydroartemisinin, DS-3078, DS-7423, duvelisib, EM-101, everolimus, FP-208, FT-1518, FXY-1, galarmin, GDC-0349, gedatolisib, GM-6, GNE-317, GNE-555, GSK-690693, GT-0486, HD-148 series, HEC-68498, HM-032, HM-5016699, HMPL-518, ipatasertib, IP I-549, ISC-4, J-9, JRP-890, KIT-2014, KS-99, LD-101, lithium carbonate, LY-2503029, LY-2780301, M-2698, ME-344, miransertib mesylate, MK-2206, MKC-1, monepantel, NISC-6, nPT-mTOR, NSC-765844, NV-128, onatasertib, ONC-201, ONC-222, ONC-235, OSU-53, OT-043, OT-043, P-7170, P-7170, PBD-1226, perifosine, PF-04691502, pimasertib hydrochloride + voxtalisib, PKI-179, PQR-311, PQR-316, PQR-401, PQR-4XX, PQR-514, PQR-530, PQR-620, PWT-33597, PX–316, recilisib sodium salt, RES-529, ridaforolimus, RMC-5552, RP-6503, RV-1729, RX-0183, RX-02 01, RX-0201N, RX-0301, RX-1792, RX-8243, samotolisib, sapanisertib, SB-2602, SCC-31, SF-1126, SF-2523, SN-202, SPR-965, SR-13668, STP-503, SX-MTR1, TAFA-93, TAM-01, TAM-03, TAS-117, TASP-0415914, TE-7105, temsirolimus, tenalisib, TOP-216, trametinib dimethyl sulfoxide + uprosertib, triciribine phosphatephosphate), UB-1201, uprosertib, VCC-405567, VCC-668662, vistusertib, VLI-27, voxtalisib, VS-5584, WX-008, WXFL-10030390, X-387, X-414, X-480, XL-388, XL-418, XP-105, Y-31, Zortress, or any combination thereof.

[0075] Unless otherwise specified, all technical terms and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present disclosure belongs. In this specification, the singular also includes the plural, unless otherwise clearly specified in the context. Although methods and materials similar or equivalent to those described herein can be used for implementing or testing the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety for all purposes. The references cited herein are not admitted to be prior art of the present disclosure for which protection is claimed. In the event of a conflict, this specification, including definitions, shall prevail. In addition, materials, methods and examples are merely illustrative and are not intended to be limiting.

[0076] Summary of the Figures

[0077] FIG1 is a graph depicting the effects of vehicle or compound 20 (labeled as compound A in the figure) on the treatment of lean ( Figure 1A and 1B ) and obesity ( Figure 1C ) Series of graphs showing the change in mammary tumor volume over time (in days) in mice responding to E0771.

[0078] FIG2 is a graph depicting the effects of treatment of lean ( Figure 2A ) or obesity ( Figure 2B ) A series of graphs showing changes in mouse body weight over time.

[0079] FIG3 is a graph depicting parametrial fat in lean and obese mice after treatment with vehicle or Compound 20 (labeled Compound A in the figure). Figure 3A ), inguinal adipose tissue ( Figure 3B ) and retroperitoneal adipose tissue ( Figure 3C ) in a series of graphs showing changes in adipose tissue mass.

[0080] FIG4 is a graph depicting leptin levels in lean and obese mice treated with vehicle or Compound 20 (labeled Compound A in the figure). Figure 4A ), adiponectin ( Figure 4B ) expression levels and leptin / adiponectin ratio (LAR) ( Figure 4C ) changes.

[0081] FIG5 is a graph depicting the effect of Compound 20 (labeled as Compound A) on the treatment of lean ( Figure 5A ) and obesity ( Figure 5B ) A series of graphs showing changes in the levels of the immunosuppressive cytokine IL10 in mice.

[0082] Figure 6 Graphs and comparisons depict changes in tumor suppressor myeloid-derived suppressor cells (MSDCs) in tumor cells from lean and obese mice following treatment with Compound 20 (labeled Compound A in the figure).

[0083] Figure 7A are images of immunohistochemically stained EO771 mammary tumors from obese vehicle-treated mice stained for the Treg marker FoxP3.

[0084] Figure 7B are images of immunohistochemically stained EO771 mammary tumors from obese mice treated with Compound 5 (labeled Compound A in the figure) stained for the Treg marker FoxP3.

[0085] Figure 8A are images of immunohistochemically stained EO771 mammary tumors from obese, vehicle-treated mice stained for the tumor-associated macrophage enzyme Arg-1.

[0086] Figure 8B Images of immunohistochemically stained EO771 mammary tumors from obese mice treated with Compound 20 (labeled Compound A in the figure) stained for the tumor-associated macrophage enzyme Arg-1.

[0087] Figure 9 is a series of graphs depicting leptin levels in the serum of cancer patients treated with Compound 20 (labeled Compound A in the graphs) as part of a clinical trial of SDX-101. Figure 9A depicts changes in leptin levels in ng / mL, while Figure 9B Changes in leptin levels as percent change from baseline are depicted.

[0088] Figure 10 is a series of graphs depicting adiponectin levels in the serum of cancer patients treated with Compound 20 (labeled Compound A in the graph) as part of a clinical trial of SDX-101. Figure 10A The changes in adiponectin levels in µg / mL are depicted, while Figure 10B Changes in adiponectin levels are depicted as percent change from baseline.

[0089] Figure 11 is a series of graphs depicting the leptin / adiponectin ratio in the serum of cancer patients treated with Compound 20 (labeled Compound A in the figures) as part of a clinical trial of SDX-101. Figure 11A The changes in the leptin / adiponectin ratio in ng / µg are depicted, while Figure 11B Changes in the leptin / adiponectin ratio as percent change from baseline are depicted.

[0090] Figure 12 is a series of graphs depicting levels of the pro-angiogenic marker VEGF-C in the serum of cancer patients treated with Compound 20 (labeled Compound A in the figures) as part of a clinical trial of SDX-101. Figure 12A The changes in VEGF-C levels in pg / mL are depicted, while Figure 12B Changes in VEGF-C levels are depicted as percent change from baseline.

[0091] Figure 13 is a series of graphs depicting the levels of the pro-angiogenic and pro-tumor marker IGF-1 in the serum of cancer patients treated with Compound 20 (labeled Compound A in the figures) as part of a clinical trial of SDX-101. Figure 13A The changes in IGF-1 levels in ng / mL are depicted, while Figure 13B Changes in IGF-1 levels are depicted as percent change from baseline.

[0092] Figure 14 is a series of graphs depicting levels of the pro-angiogenic biomarker bFGF / FGF2 in the serum of cancer patients treated with Compound 20 (labeled Compound A in the figures) as part of a clinical trial of SDX-101. Figure 14A The changes in bFGF / FGF2 levels in pg / mL are depicted, while Figure 14B Changes in bFGF / FGF2 levels are depicted as percent change from baseline.

[0093] Figure 15 shows the effect of Compound 20 (labeled Compound A in the figure) on insulin levels in heavily pretreated cancer patients with baseline insulin levels above 20 uU / ml. The graph depicts absolute values ​​(left) and percent change (right).

[0094] Figure 16 Attenuation of blood glucose spikes in a mouse model of PI3K inhibitor-mediated hyperglycemia is shown, in which normal C57Bl / 6 mice were dosed with a PI3K inhibitor to induce hyperglycemia and pretreated with compound 20 (labeled Compound A in the figure) 10 days prior to a four-day dosing schedule, or 24 hours prior to injection with the PI3K inhibitor, or 4 hours prior to injection with the PI3K inhibitor.

[0095] Figure 17 The results show that the cultured human lymphoblastoid cell line TK6 (2×10 5 cells / ml seeded) over a 16-hour (upper panel) and 24-hour (lower panel) time course to increase apoptosis.

[0096] Figure 18 Shown is the induction of caspase 3 / 7 markers of apoptosis over time (16 h, upper panel; 24 h, lower panel) in cultured human lymphoblastoid cell line TK6, which was treated with 2×10 5 cells / ml and treated with the disclosed small molecule fumagillin derivatives.

[0097] Figure 19 The results show an overall improvement in insulin resistance in cancer patients treated with compound 20, calculated using the HOMA2-IR scoring method. Most of these advanced cancer patients did not have obvious metabolic dysfunction, which indicates a surprising effect of improving insulin resistance in cancer patients.

[0098] Figure 20 Shown is a surprising time course reduction in insulin in metabolically normal mice treated with a drug from the PI3K class of therapeutics (BYL-719) in combination with Compound 20 (shown as Compound A in the figure) and developed hyperglycemia as a result of PI3K treatment.

[0099] Figure 21 Shown is a surprising time-course reduction in C-peptide in metabolically normal mice treated with a drug from the PI3K drug class therapeutics (BYL-719) in combination with Compound 20 (shown as Compound A in the figure) and developed hyperglycemia as a result of PI3K treatment.

[0100] Figure 22 is a graph showing the change in MCF-7 tumor volume (% change from baseline) in mice treated with vehicle control, 8 mg / kg of Compound 20 (referred to as Compound A), or 16 mg / kg of Compound 20.

[0101] Figure 23 is a graph showing the change in MCF-7 tumor volume (% change from baseline) in mice treated with vehicle control, 8 mg / kg of Compound 20 (referred to as Compound A), 8 mg / kg of Compound 20 in combination with 25 mg / kg of BYL-719, or 25 mg / kg of BYL-719 alone.

[0102] Figure 24is a graph showing the change in MCF-7 tumor volume (% change from baseline) in mice treated with vehicle control, 8 mg / kg of Compound 20 (referred to as Compound A), 8 mg / kg of Compound A in combination with 45 mg / kg of BYL-719, or 45 mg / kg of BYL-719 alone.

[0103] Figure 25 is a graph showing changes in tumor volume at day 37 in mice treated with vehicle control, Compound 20 alone (referred to as Compound A), BYL-719 alone, or a combination of Compound 20 and BYL-719.

[0104] Figure 26 is a graph showing glucose levels in mice treated with Compound 20 (referred to as Compound A) alone, the Akt inhibitor AZD5363 alone, or a combination of Compound 20 and AZD5363.

[0105] Figure 27 is a graph showing blood glucose levels in mice treated with vehicle control or the PI3K inhibitor BYL-719.

[0106] Figure 28 is a graph showing blood glucose levels in mice treated with vehicle control, ZGN-1061 alone, BYL-719 alone, or a combination of ZGN-1061 and BYL-719. Detailed Description of the Invention

[0108] The present disclosure provides methods for inducing or causing beneficial changes in various cells, tissues and / or proteins that would otherwise hinder the clinical activity of various cancer treatments.In certain aspects, the subject is overweight, obese or has a metabolic dysfunction as a pre-existing condition or triggered by certain secondary agents.

[0109] The present disclosure provides methods for mitigating or preventing the negative systemic effects of certain cancer therapies on a patient's metabolic system. For example, certain cancer therapies induce hyperglycemia and subsequent hyperinsulinemia, which may diminish their efficacy. The MetAP2 inhibitors disclosed herein can mitigate or prevent the negative metabolic effects of these cancer therapies and, therefore, improve tumor treatment outcomes in subjects in need thereof, comprising administering to a subject at least one compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, in a therapeutically effective amount according to a reasonable regimen to treat or mitigate these underlying disease-modifying factors and improve treatment outcomes.

[0110] The present disclosure also provides methods for altering the tumor microenvironment in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in a therapeutically effective amount according to a reasonable regimen so as to enhance the effect of the co-administered therapy in treating or alleviating these diseases and conditions.

[0111] The present disclosure also provides methods for reducing certain pro-angiogenic factors associated with obesity or cancer.Herein, it is shown for the first time that MetAP2 inhibitors can also inhibit angiogenesis via systemic reduction of the pro-angiogenic factors VEGF-C, bFGF and IGF-1.

[0112] How to use

[0113] The present disclosure provides a method for treating a proliferative disorder or alleviating at least one symptom of a proliferative disorder in a subject in need thereof, comprising administering to the subject at least one MetAP2 inhibitor in a therapeutically effective amount, wherein the expression of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, PD-1, PD-L1, CTLA-4, VEGF-C, IGF-1, and bFGF is reduced in the tumor, in the tumor microenvironment, in plasma, or in any combination thereof in the subject having cancer. In a preferred aspect, the proliferative disorder is cancer. The cancer can be HR+ / Her2- breast cancer, triple-negative breast cancer, Her2+ breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal carcinoma, melanoma, multiple myeloma, or a combination thereof. The subject may also be overweight or obese. The subject may have a metabolic dysfunction comprising any of the following: excess visceral fat, elevated leptin levels, decreased adiponectin levels, a high leptin / adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, or a combination thereof. The methods of the present disclosure may further comprise treating or alleviating at least one symptom of the metabolic dysfunction in addition to treating or alleviating at least one symptom of the proliferative disorder.

[0114] The present disclosure provides a method for treating or alleviating at least one symptom of metabolic dysfunction associated with cancer treatment in a subject, comprising administering at least one MetAP2 inhibitor in a therapeutically effective amount. The cancer can be HR+ / Her2- breast cancer, triple-negative breast cancer, Her2+ breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, or multiple myeloma. The subject may also be overweight or obese. Metabolic dysfunction can include excess visceral fat, elevated leptin levels, decreased adiponectin levels, a high leptin / adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, hyperglycemia, or a combination thereof. The methods of the present disclosure can also include treating or alleviating at least one symptom of metabolic dysfunction in addition to treating or alleviating at least one symptom of a proliferative disorder.

[0115] The present disclosure provides methods of reducing IL-10 expression in a tumor or in systemic circulation (i.e., blood, plasma, or serum) in a subject having cancer, comprising administering at least one MetAP2 inhibitor in a therapeutically effective amount to a subject having a metabolic dysfunction, wherein IL-10 expression in the tumor or plasma is reduced in the subject having cancer.

[0116] The present disclosure provides methods of reducing the expression of arginase-1 in a tumor, in the tumor microenvironment, or in the systemic circulation (i.e., blood, plasma, or serum) in a subject having cancer, comprising administering at least one MetAP2 inhibitor in a therapeutically effective amount to a subject having a metabolic dysfunction, wherein the expression of arginase-1 in the tumor or plasma is reduced in the subject having cancer.

[0117] The present disclosure provides methods for reducing the expression of myeloid-derived suppressor cells in a tumor or in the systemic circulation (i.e., blood) in a subject having cancer, comprising administering at least one MetAP2 inhibitor in a therapeutically effective amount to a subject having a metabolic dysfunction, wherein the expression of myeloid-derived suppressor cells in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0118] The present disclosure provides a method of reducing the expression of regulatory T cells in a tumor or in systemic circulation (i.e., blood) in a subject having cancer, comprising administering at least one MetAP2 inhibitor in a therapeutically effective amount to a subject having a metabolic dysfunction, wherein the expression of regulatory T cells in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0119] The present disclosure provides methods of reducing leptin expression in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one MetAP2 inhibitor in a therapeutically effective amount, wherein leptin expression in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0120] The present disclosure provides a method for reducing the expression of a growth factor in a tumor or in the systemic circulation (i.e., blood, plasma, or serum) in a subject suffering from cancer, comprising administering at least one MetAP2 inhibitor in a therapeutically effective amount to a subject suffering from a metabolic dysfunction, wherein the expression of the growth factor in the tumor, tumor microenvironment, or plasma is reduced in the subject suffering from cancer. The growth factor can be VEGF-C, IGF-1, bFGF, or a combination thereof.

[0121] The present disclosure provides methods for treating or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering to the subject at least one fumagillin analog or derivative or a reversible MetAP2 inhibitor in a therapeutically effective amount, wherein the expression of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, insulin, VEGF-C, IGF-1, or bFGF in the tumor, in the tumor microenvironment, or in the plasma is reduced and / or the level of the hormone adiponectin is increased in the subject having cancer.

[0122] The present disclosure provides methods for treating or alleviating at least one symptom of metabolic dysfunction associated with cancer treatment in a subject having cancer, comprising administering to the subject at least one fumagillin analog or derivative or conjugate in a therapeutically effective amount to treat or alleviating at least one symptom of metabolic dysfunction associated with cancer treatment in the subject.

[0123] The present disclosure provides methods of reducing IL-10 expression in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one fumagillin analog or derivative in a therapeutically effective amount, wherein IL-10 expression in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0124] The present disclosure provides methods of reducing arginase-1 expression in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one fumagillin analog or derivative in a therapeutically effective amount, wherein arginase-1 expression in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0125] The present disclosure provides methods of reducing the expression of myeloid-derived suppressor cells in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one fumagillin analog or derivative in a therapeutically effective amount, wherein the expression of myeloid-derived suppressor cells in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0126] The present disclosure provides a method for reducing the expression of regulatory T cells in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one fumagillin analog or derivative in a therapeutically effective amount, wherein the expression of regulatory T cells in the tumor or plasma or tumor microenvironment is reduced in the subject having cancer. The present disclosure provides a method for reducing the expression of leptin in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one fumagillin analog or derivative in a therapeutically effective amount, wherein the expression of leptin in the tumor, tumor microenvironment or plasma is reduced in the subject having cancer.

[0127] The present disclosure provides a method for reducing the expression of a growth factor in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one fumagillin analog or derivative in a therapeutically effective amount, wherein the expression of the growth factor in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer. The growth factor can be VEGF-C, IGF-1, bFGF, or a combination thereof.

[0128] The present disclosure provides methods of treating or alleviating at least one symptom of cancer in a subject in need thereof, comprising administering to the subject at least one compound of the present disclosure in a therapeutically effective amount, wherein the expression of at least one of IL-10, arginase-1, myeloid-derived suppressor cells (MDSCs), regulatory T cells, leptin, insulin, VEGF-C, IGF-1, or bFGF in a tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0129] The present disclosure provides methods of treating or alleviating at least one symptom of metabolic dysfunction associated with cancer treatment in a subject having cancer, comprising administering to the subject at least one compound of the present disclosure in a therapeutically effective amount to treat or alleviating at least one symptom of metabolic dysfunction associated with cancer treatment in the subject having cancer.

[0130] The present disclosure provides methods of reducing IL-10 expression in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one compound of the present disclosure in a therapeutically effective amount, wherein the expression of IL-10 in the tumor, tumor microenvironment, or plasma is reduced in the metabolically dysfunctional subject having cancer.

[0131] The present disclosure provides methods of reducing arginase-1 expression in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one compound of the present disclosure in a therapeutically effective amount, wherein arginase-1 expression in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0132] The present disclosure provides methods of reducing the expression of myeloid-derived suppressor cells in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one compound of the present disclosure in a therapeutically effective amount, wherein the expression of myeloid-derived suppressor cells in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0133] The present disclosure provides methods of reducing expression of regulatory T cells in a tumor or plasma in a subject having cancer, comprising administering to the subject at least one compound of the present disclosure in a therapeutically effective amount, wherein expression of regulatory T cells in the tumor, tumor microenvironment, or plasma is reduced in the subject having cancer.

[0134] The present disclosure provides a method for reducing the expression of a growth factor in a tumor or plasma in a subject suffering from cancer, comprising administering to the subject at least one compound of the present disclosure in a therapeutically effective amount, wherein the expression of the growth factor in the tumor, tumor microenvironment, or plasma is reduced in the subject suffering from cancer. The growth factor can be VEGF-C, IGF-1, bFGF, or a combination thereof.

[0135] Obesity has been identified as a risk factor for breast cancer, and excess visceral adipose tissue is associated with a poorer response to chemotherapy and decreased progression and / or disease-free survival (Schaffler, A. et al., (2007) Nat Clin Pract Endocrinol Metab 3:345-54; Vona-Davis, L. Rose, D P. (2007) Endocr Relat Cancer 14:189-206). Adipose tissue-derived factors (e.g., leptin, adiponectin, aromatase, IL-6) have been proposed as possible mediators of the obesity-breast cancer link, with recent data particularly focusing on the adipokines leptin and adiponectin (Cleary, MP et al., (2009) Front Biosci (School Ed) 1:329-57; Cleary, MP et al., (2010) Vet Pathol 47:202-13). The molecular basis for the actions of leptin, adiponectin, and other hormones, such as insulin and insulin-like growth factor, has recently been described. Circulating adiponectin levels are inversely correlated with body mass index (BMI); in contrast, serum leptin is directly proportional to BMI (Ryan, A S. et al., (2003) Diabetes Care 26:2383-8; Wauters, M. et al., (2000) Eur J Endocrinol 143:293-311). In obese individuals, particularly those with high visceral fat content, adiponectin levels are suppressed (Brochu-Gaudreau K et al., Endocrine 2010, 37(1):11-32). Adiponectin is present in human serum at concentrations of 2-20 μg / ml (Grossmann, M E. et al., (2008) Br J Cancer 98:370-9). The mechanism underlying adiponectin signaling and cancer prevention is thought to involve activation of the intracellular signaling AMPK and inhibition of growth and survival pathways (Brochu-Gaudreau K et al., Endocrine 2010, 37(1):11-32; Pfeiler G et al., Maturitas 2009, 63(3):253-256). In addition, adiponectin can indirectly exert its biological activity by selectively sequestering different growth factors (e.g., basic fibroblast growth factor, platelet-derived growth factor BB, heparin-binding epidermal growth factor) and inhibiting their normal receptor binding.These interactions involve specific oligomeric forms of adiponectin (Barb, D., Williams, C J., Neuwirth, AK., Mantzoros, CS. (2007) Am J Clin Nutr 86:s858-66; Wang et al., (2005) J Biol Chem 280:18341-7).

[0136] Several epidemiological studies have found an inverse relationship between adiponectin levels and breast cancer risk (Barb et al., (2007) Am J Clin Nutr 86:s858-66; Miyoshi et al., (2003) Clin Cancer Res 9:5699-704; Mantzoros et al., (2004) J Clin Endocrinol Metab 89:1102-7; Chen, D C. et al., (2006) Cancer Lett 237:109-14). In breast cancer patients, adiponectin levels and the adiponectin / leptin ratio tend to be lower than those found in lean women (Cleary MP et al., (2009) Front Biosci (Schol Ed) 1:329-57; Cleary, MP et al., (2006) Cancer Lett 237:109-14). Breast cancer patients with low adiponectin levels have been reported to have more aggressive tumors and a higher frequency of lymph node metastases (Schaffler, A. et al., (2007) Nat Clin Pract Endocrinol Metab 3:345-54; Hou, W K. et al., (2007) ChinMed J (Engl) 120:1592-6).

[0137] In one aspect, the present disclosure provides methods for treating specific tumor types exacerbated by metabolic dysfunction using at least one MetAP2 inhibitor, at least one fumagillin analog or derivative, and / or at least one compound of the present disclosure, including HR+ / Her2- breast cancer, triple-negative breast cancer, Her2+ breast cancer, invasive breast cancer, castration-resistant prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal cell carcinoma, melanoma, multiple myeloma, or acute myeloid leukemia. In a preferred aspect, the present method discloses subcutaneous administration of a MetAP2 inhibitor in cancer patients with pre-existing or treatment-induced metabolic dysfunction. Metabolic dysfunction can include excess visceral fat, elevated leptin levels, decreased adiponectin levels, a high leptin / adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. This approach may restore the patient to a more metabolically neutral and stable state and slow or reverse the progression of the patient's cancer.

[0138] Described herein are methods for improving underlying metabolic dysfunction in patients with metabolically sensitive tumors. The methods for treating tumors include increasing adiponectin levels, decreasing leptin levels, improving (or decreasing) the leptin / adiponectin ratio, decreasing insulin levels, decreasing fasting blood glucose levels, or a combination thereof. Subcutaneously administered MetAP2 inhibitors described herein have been shown to improve these levels and ratios in cancer patients and, therefore, may be used to treat metabolically sensitive tumors, which may benefit from upregulation of adiponectin and improved leptin and insulin sensitivity. Therefore, in certain aspects, the MetAP2 inhibitors described herein may be used to treat cancers including hormone receptor-positive (HR+) breast cancer, triple-negative breast cancer, Her2+ breast cancer, castration-resistant prostate cancer, esophageal adenocarcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, hepatocellular carcinoma, clear cell renal cell carcinoma, melanoma, multiple myeloma, or a combination thereof. These cancers may be at least partially related to adiponectin deficiency and / or adiponectin resistance.

[0139] The present disclosure also provides a method for treating cancer in a subject in need thereof, the method comprising the steps of: (i) identifying the patient as having hormone receptor-positive (HR+) breast cancer, triple-negative breast cancer, Her2+ breast cancer, castration-resistant prostate cancer, esophageal adenocarcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, hepatocellular carcinoma, clear cell renal carcinoma, melanoma, multiple myeloma, or acute myeloid leukemia; (ii) determining whether the cancer patient has a metabolic dysfunction, and (iii) if the subject is identified as having one of the cancers in step (i) and is identified as having a metabolic dysfunction in step (ii), administering a therapeutically effective amount of at least one MetAP2 inhibitor, at least one fumagillin analog or derivative, or at least one compound of the present disclosure. Preferably, the compound of the present disclosure is administered to the subject. Preferably, the compound is administered subcutaneously. Metabolic dysfunction can include excess visceral fat, elevated leptin levels, decreased adiponectin levels, a high leptin / adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. Preferably, the metabolic dysfunction is low adiponectin, elevated leptin, elevated fasting insulin, hyperglycemia, or a combination thereof. The methods of the present disclosure can also include treating or alleviating at least one symptom of the metabolic dysfunction in addition to treating cancer.

[0140] In another aspect, the present disclosure provides a method for determining whether a tumor is metabolically sensitive, comprising: (1) identifying the tumor type as one of a list of known metabolically sensitive tumors (meningioma, thyroid cancer, esophageal adenocarcinoma, liver cancer, gallbladder cancer, GIST, pancreatic cancer, kidney cancer, CRC, prostate cancer, multiple myeloma, breast cancer, ovarian cancer, cervical cancer, endometrial cancer), (2) measuring fasting insulin and glucose levels to determine the patient's HOMA score (insulin sensitivity level), (3) comparing the HOMA score to that of lean patients, and (4) if the HOMA score is at a level greater than a metabolically normal level, determining that the cancer is susceptible to treatment with at least one MetAP2 inhibitor, at least one fumagillin analog or derivative, or at least one compound of the present disclosure.

[0141] In another aspect, the present disclosure provides methods for co-administering a MetAP2 inhibitor with a treatment that induces metabolic dysfunction. The treatment can be a cancer treatment. The treatment can be an AKT inhibitor, a PI3K inhibitor, an mTOR inhibitor, a PI3K / AKT / mTOR pathway inhibitor, or any combination thereof.

[0142] As used herein, a "subject in need thereof" is a subject having a cell proliferative disorder, or a subject at increased risk of developing a cell proliferative disorder relative to the general population. A subject in need thereof may have a precancerous condition, such as hyperplasia. Preferably, the subject in need thereof has cancer or a metastasis from a primary cancerous tumor or a hematologic cancer. Preferably, the subject having a cell proliferative disorder also has a pre-existing or treatment-induced metabolic dysfunction.

[0143] "Subject" includes mammals. The mammal can be, for example, any mammal, such as a human, a primate, a mouse, a rat, a dog, a cat, a cow, a horse, a goat, a rabbit, a camel, a sheep, or a pig. Preferably, the mammal is a human. The terms "subject" and "patient" are used interchangeably herein.

[0144] As used herein, the term "cell proliferative disorder" refers to a condition in which unregulated and / or abnormal growth of cells may lead to the development of an undesirable condition or disease (which may or may not be cancerous). Exemplary cell proliferative disorders disclosed herein encompass a variety of conditions in which cell division is dysregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, B-cell lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cell" is defined as any cell that divides at a rate that exceeds or is greater than that expected or observed in adjacent or juxtaposed cells within the same tissue. Cell proliferative disorders include precancerous or precancerous conditions. Cell proliferative disorders include cancer or metastasis from a primary cancerous mass. Cell proliferative disorders include non-cancerous conditions or illnesses. Preferably, the methods provided herein are used to treat or alleviate the symptoms of cancer. The term "cancer" includes solid tumors, as well as hematological tumors and / or malignancies or metastases from primary cancerous masses or blood sources. "Precancerous cells" or "precancerous cells" are cells that exhibit a cell proliferative disorder that is a precancerous or precancerous state. "Cancer cells" or "cancerous cells" are cells that exhibit a cell proliferative disorder that is a cancer. As used herein, the terms "metastasis," "metastatic cancer," or "metastatic lesions" refer to the development of secondary malignant growths at a distance from the primary site of cancer. Any reproducible measurement method can be used to identify cancerous or precancerous cells. Cancerous or precancerous cells can be identified by histological typing or grading of tissue samples (e.g., biopsy samples), or by evidence of DNA mutations. Cancerous or precancerous cells can be identified by using appropriate molecular markers.

[0145] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, B-cell lymphomas, anal cancer, anorectal cancer, anal canal cancer, anal squamous cell carcinoma, angiosarcoma, appendix cancer, childhood cerebellar astrocytoma, childhood brain astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, allantoic cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumors, brain stem gliomas, cerebellar astrocytoma, brain astrocytoma / malignant glioma Tumors, ependymomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, optic pathway and hypothalamic gliomas, breast cancer, bronchial adenomas / carcinoids, carcinoid tumors, gastrointestinal tract, nervous system cancers, nervous system lymphomas, central nervous system cancers, central nervous system lymphomas, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphomas, lymphoid neoplasms, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell Tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, ovarian germ cell tumors, gestational trophoblastic tumors, gliomas, head and neck cancer, head and neck squamous cell carcinoma, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreatic tumor), Kaposi's sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, T-cell lymphocytic leukemia Leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, squamous cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, B-cell lymphoma, primary effusion lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myeloproliferative syndrome, myeloproliferative / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancercancer), oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, pancreatic endocrine tumors, sinus and nasal cavity cancer, parathyroid cancer, bile duct cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pituitary adenoma, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's disease family of sarcomas, Kaposi sarcoma, soft tissue sarcomas, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, laryngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0146] A "hematologic cell proliferative disorder" is a cell proliferative disorder involving cells of the hematologic system. Cell proliferative disorders of the hematologic system may include lymphoma, B-cell lymphoma, leukemia, myeloid neoplasms, mast cell tumors, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelogenous leukemia, idiopathic extramedullary metaplasia, and essential thrombocythemia. Cell proliferative disorders of the hematologic system may include hyperplasia, dysplasia, and metaplasia of hematologic cells. Preferably, the compositions of the present disclosure can be used to treat a cancer selected from the hematologic cancers of the present disclosure or the hematologic cell proliferative disorders of the present disclosure. The hematological cancers of the present disclosure may include multiple myeloma, lymphomas (including Hodgkin lymphoma, non-Hodgkin lymphoma, childhood lymphoma, and lymphomas of lymphocytic and cutaneous origin), leukemias (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, and mast cell leukemia), myeloid tumors, and mast cell tumors.

[0147] A cancer that is to be treated can be graded according to the American Joint Committee on Cancer (AJCC) TNM classification system, wherein the tumor (T) has been assigned a grade of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and wherein regional lymph nodes (N) have been assigned a grade of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and wherein distant metastases (M) can be assigned a grade of MX, M0, or M1. A cancer that is to be treated can be graded according to the American Joint Committee on Cancer (AJCC) classification as Grade I, Grade IIA, Grade IIB, Grade IIIA, Grade IIIB, Grade IIIC, or Grade IV. A cancer that is to be treated can be assigned a grade of Grade GX (e.g., unable to assess grade), Grade 1, Grade 2, Grade 3, or Grade 4 according to the AJCC classification. A cancer to be treated can be graded according to the AJCC pathology classification (pN) as pNX, pN0, PN0(I-), PN0(I+), PN0(mol-), PN0(mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0148] A cancer that is to be treated may include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. A cancer that is to be treated may include a tumor that has been determined to be between about 2 and about 5 centimeters in diameter. A cancer that is to be treated may include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. A cancer that is to be treated may include a tumor that has been determined to be greater than 5 centimeters in diameter. A cancer that is to be treated may be classified by microscopic appearance as well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated. A cancer that is to be treated may be classified by microscopic appearance as having mitotic count (e.g., the amount of cell division) or nuclear pleomorphism (e.g., changes in cells). A cancer that is to be treated may be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells). A cancer that is to be treated may be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance. A cancer that is to be treated may be classified as aneuploid, triploid, tetraploid, or as having altered ploidy. A cancer that is to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication, or amplification of a portion of a chromosome.

[0149] A cancer to be treated can be assessed by DNA cytometry, flow cytometry, or image cytometry. A cancer to be treated can be classified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis phase of cell division (e.g., in the S phase of cell division). A cancer to be treated can be classified as having a low S phase fraction or a high S phase fraction.

[0150] As used herein, a "normal cell" is a cell that cannot be classified as part of a "cell proliferative disorder." A normal cell does not have unregulated and / or abnormal growth (which could lead to the development of an undesirable condition or disease). Preferably, a normal cell has normally functioning cell cycle checkpoint control mechanisms.

[0151] As used herein, "contacting a cell" refers to a situation in which a compound or other composition of the presently disclosed subject matter is in direct contact with a cell, or close enough to induce a desired biological effect in the cell.

[0152] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may also treat or alleviate a variety of related conditions.

[0153] In particular, in addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also treat or alleviate at least one metabolic dysfunction selected from excess visceral fat, elevated leptin levels, decreased adiponectin levels, a high leptin / adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels with chronic inflammation, hyperglycemia, elevated HbA1c, or a combination thereof. Preferably, the metabolic dysfunction treated or alleviated is low adiponectin, elevated leptin, elevated fasting insulin, hyperglycemia, or a combination thereof.

[0154] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure may also treat or alleviating at least one symptom of obesity or treatment-induced metabolic dysfunction.

[0155] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce body weight. In some aspects, the subject is overweight or obese. In some aspects, the subject needs to reduce excess adipose tissue. Preferably, the adipose tissue reduced is visceral adipose tissue or adipose tissue near a tumor or metastasis.

[0156] Obesity and overweight refer to an excess of fat mass relative to lean body mass in a subject. Excess fat accumulation is associated with an increase in the size (hypertrophy or steatosis) and number (hyperplasia) of adipose tissue cells. Obesity may be due to any cause, whether genetic (e.g. Prader-Willi syndrome) or environmental. Obesity is measured in different ways based on absolute weight, weight:height ratio, degree of excess body fat, distribution of visceral or subcutaneous fat. A common measure of body fat is the body mass index (BMI). BMI is the ratio of weight (expressed in kilograms) to height (expressed in meters) squared. Body mass index can be calculated precisely using the following formula: SI units: BMI = weight (kg) / (height 2 (m 2)), or in US units: BMI=(weight (lb)*703) / (height 2 (in 2 )).

[0157] As used herein, "overweight" refers to an otherwise healthy adult with a weight of 25 kg / m 2 Up to 29.9 kg / m 2 As used herein, "obesity" or "obesity" refers to a condition whereby an otherwise healthy adult has a BMI of 30 kg / m 2 A BMI of 35 kg / m2 or greater. Obesity has several subcategories. 2 Adults with a BMI of ≥40-44.9 kg / m2 or higher are considered "severely obese" or "severely obese." 2 Adults with a BMI of 35 kg / m 2 Adults with a BMI of 45 kg / m2 or higher and at least one obesity-related health condition are termed "morbidly obese" or "morbidly obese." 2 Adults with a body weight of 100 or more are considered "super obese" or "very obese." For children, the definitions of overweight and obesity take into account the effects of age and sex on body fat.

[0158] Different countries may use different BMI definitions for obesity and overweight. The term "obesity" is intended to encompass all national definitions. For example, the increased risk associated with obesity occurs at lower body mass indexes (BMIs) in Asian populations. In Asian countries, including Japan, "obesity" refers to a body mass index greater than or equal to 25.0 kg / m2 in subjects with at least one obesity-induced or obesity-related comorbidity that requires or would be ameliorated by weight loss. 2 South and Central Americans tend to be classified closer to Asians than to Europeans or North Americans.

[0159] The BMI does not take into account the fact that excess fat tissue may selectively appear in different parts of the body and that the development of fat tissue may be more dangerous to health in some parts of the body than in other parts of the body. For example, "central obesity" (often associated with an "apple-shaped" body shape) is caused by excess fat (especially in the abdominal area, including abdominal fat and visceral fat) and carries a higher risk of comorbidities than "peripheral obesity" (which is often associated with a "pear-shaped" body shape caused by excess fat (especially in the hips)). Measurement of the waist / hip ratio (WHR) can be used as an indicator of central obesity. The minimum WHR indicating central obesity has been set differently, with centrally obese adults generally having a WHR of approximately 0.85 or greater if they are female and approximately 0.9 or greater if they are male.

[0160] Methods for determining whether a subject is overweight or obese by considering the ratio of excess adipose tissue to lean body mass can include obtaining the subject's body composition. Body composition can be obtained by measuring the thickness of subcutaneous fat at various locations on the body, such as the abdominal area, subscapular area, arms, buttocks, and thighs. These measurements are then used to estimate total body fat with a margin of error of approximately 4 percentage points. Another method is bioelectrical impedance analysis (BIA), which uses the resistance of an electric current passing through the body to estimate body fat. Another method is to measure body buoyancy using a large jug of water. Increased body fat will result in greater buoyancy, while greater muscle mass will result in a tendency to sink. Another method is fan-beam dual-energy X-ray absorptiometry (DEXA). DEXA allows for the non-invasive determination of body composition, particularly total body fat mass and / or regional fat mass. MRI can also be used to non-invasively determine composition.

[0161] In another instance, the present invention can alleviate the symptoms of a second or other treatment-induced metabolic dysfunction.In a preferred embodiment, the additional agent is a PI3K, AKT or mTOR inhibitor.

[0162] In another instance, the subject can be pretreated with a compound of the invention for 1 hour, 4 hours, 1 day, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 8 weeks.

[0163] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce adipocytes or adipose tissue. Reducing adipocytes means reducing the number of adipocytes or reducing the size (fat content) of adipocytes. In certain aspects, the compounds of the present disclosure shrink adipocytes in a subject. The adipose tissue can be white adipose tissue or brown adipose tissue.

[0164] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce waist circumference. Waist circumference is assessed using a tape measure placed around the abdomen 1 cm above the iliac crest. A subject's waist circumference can be reduced by about 1 inch to about 20 inches (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 inches).

[0165] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce the patient's body fat and provide substantial maintenance of muscle mass. In some aspects, after administration, fat oxidation in the patient's body is enhanced compared to patients on a restricted food intake diet alone. Compared to the reduction in body fat in patients on an energy restricted diet alone, such patients can retain significantly more muscle mass.

[0166] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also reduce insulin levels and / or leptin levels in a subject. In some aspects, the subject is overweight or obese, or has elevated fasting insulin and / or leptin. In some aspects, the subject needs to reduce excess adipose tissue.

[0167] In addition to treating or alleviating at least one symptom of one or more proliferative disorders, the compounds of the present disclosure can also improve surgical outcomes, including administering at least one compound of the present disclosure to a subject in a therapeutically effective amount before surgery to improve surgical outcomes. In some aspects, administration reduces the patient's liver and / or abdominal fat and improves surgical outcomes. In some aspects, the surgery is non-acute. Such surgeries can include bariatric surgery, cardiovascular surgery, abdominal surgery, or plastic surgery.

[0168] As used herein, "monotherapy" refers to the administration of a single active compound or therapeutic compound of the present disclosure to a subject in need thereof. For example, a cancer monotherapy is administered to a subject in need of treatment for cancer using one of the compounds of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. As described below, monotherapy can be contrasted with combination therapy, in which a combination of multiple active compounds is administered. In one aspect, monotherapy using a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, is more effective than combination therapy in inducing a desired biological effect.

[0169] As used herein, "combination therapy" or "co-therapy" includes the administration of at least two compounds of the present disclosure, or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof, as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of the at least two compounds of the present disclosure. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions resulting from the combination of the at least two compounds of the present disclosure. The combined administration of the at least two compounds of the present disclosure is typically carried out over a specified time period (typically minutes, hours, days, or weeks, depending on the combination selected). "Combination therapy" may (but is not typically) intended to encompass the administration of two or more compounds of the present disclosure as part of a separate monotherapy regimen that incidentally or arbitrarily results in a combination of the present disclosure.

[0170] "Combination therapy" also includes administering the compounds of the present disclosure in combination with a second active agent and / or non-drug therapy (e.g., exercise, diet, surgery, or radiation therapy). Where the combination therapy further includes a non-drug therapy, the non-drug therapy may be administered at any appropriate time, as long as a beneficial effect is achieved from the combined effects of the therapeutic agent and the non-drug therapy. For example, in appropriate circumstances, a beneficial effect may still be achieved when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, perhaps over several days or even weeks. The second active agent may be conjugated to a polymer.

[0171] "Combination therapy" is intended to encompass the administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at different times, and at least two of these therapeutic agents or therapeutic agents are administered in a substantially simultaneous manner. The substantially simultaneous manner used herein is to administer at least two therapeutic agents within 2 hours of each other. For example, substantially simultaneous administration can be achieved by administering to the subject a single composition of each therapeutic agent with a fixed ratio or in the form of a separate capsule of each therapeutic agent. The sequential manner used herein is to administer another of at least two therapeutic agents more than two hours after administering one of the at least two therapeutic agents. Preferably, for sequential administration, another therapeutic agent is administered at least 12 hours, at least 24 hours, at least 48 hours, at least 96 hours, at least one week, at least two weeks, at least four weeks, or at least eight weeks after administering one of the at least two therapeutic agents. The sequential administration or substantially simultaneous administration of each therapeutic agent can be carried out by any appropriate route, including but not limited to oral route, intravenous route, subcutaneous route, intramuscular route, and direct absorption by mucosal tissue. The therapeutic agent can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination can be administered by subcutaneous injection, while the other therapeutic agents of the combination can be administered orally or intravenously. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by subcutaneous injection. The order in which the therapeutic agents are administered is not critical for some agents.

[0172] In a preferred aspect, the second active agent is a chemotherapeutic agent or a targeted agent. In a preferred embodiment, the additional chemotherapeutic agent or targeted agent (also known as an anti-tumor agent or anti-proliferative agent) may include 5FU or its oral form capecitabine, or an agent selected from the PI3K, AKT, and mTOR drug classes.

[0173] In some aspects, the second active agent is a compound that induces metabolic dysfunction. In some aspects, the second active agent is a PI3K inhibitor, an AKT inhibitor, an mTOR inhibitor, or a PI3K / AKT / mTOR pathway inhibitor. In some aspects, the second active agent is alpelisib / BYL-719, AZD5363 (capavasertib), everolimus, or any combination thereof.

[0174] In some aspects, BYL-719 can be administered orally (PO) to a subject. In some aspects, BYL-719 can be administered once daily. In some aspects, BYL-719 can be administered in an amount of 150 mg per day. In some aspects, BYL-719 can be administered in an amount of 200 mg per day. In some aspects, BYL-719 can be administered in an amount of 250 mg per day. In some aspects, BYL-719 can be administered in an amount of 300 mg per day.

[0175] The present disclosure provides methods of treating cancer or alleviating at least one symptom of cancer in a subject in need thereof comprising administering at least one therapeutically effective amount of at least one MetAP2 inhibitor in combination with at least one therapeutically effective amount of at least one PI3K inhibitor.

[0176] In some aspects of the methods of the present disclosure, at least one MetAP2 inhibitor can be ZGN-1061. ZGN-1061 has the following structure:

[0177] .

[0178] In some aspects of the methods of the present disclosure, at least one MetAP2 inhibitor can be Beloranib. Beloranib has the following structure:

[0179] .

[0180] In some aspects of the methods of the present disclosure, at least one PI3K inhibitor can be Serabelisib (TAK-117). Serabelisib (TAK-117) has the following structure:

[0181] .

[0182] In some aspects of the methods of the present disclosure, at least one PI3K inhibitor can be BYL-719. BYL-719 has the following structure:

[0183] .

[0184] In some aspects of the present disclosure, the MetAP2 inhibitor may include, but is not limited to, A832234, JNJ4929821, a triazolopyrimidine, A357300, LAF389, an indazole, a triazole fumgalone, ZGN-1061, CKD-732, XMT-1191, TNP-470, PPI-2458, or any combination thereof.

[0185] In some aspects of the present disclosure, the MetAP2 inhibitor can have any of the following structures:

[0186]

[0187]

[0188] , ,or

[0189] , ,

[0190] ,

[0191] ,

[0192] , .

[0193] In another aspect of the present disclosure, severity describes the extent to which a tumor secretes growth factors, breaks down the extracellular matrix, becomes vascularized, loses adhesion to adjacent tissues, or metastasizes. Additionally, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of varying types and locations. In these instances, delaying the recurrence of cancer, slowing the progression of cancer, extending a subject's life expectancy and / or alleviating pain and / or improving quality of life, reducing the proportion of cancer cells or confining cells to a system, and improving cancer stage / tumor grade / histological grade / nuclear grade are considered to alleviate signs or symptoms of cancer.

[0194] As used herein, the term "symptom" is defined as an indication of a disease, disorder, injury, chronic or acute discomfort, or something not right in the body. A symptom is felt or noticed by the individual experiencing the symptom but may not be readily apparent to others. Others are defined as non-healthcare professionals.

[0195] The term "sign" as used herein is also defined as an indication that something is wrong in the body. A sign is defined as an event that can be noticed by a doctor, nurse or other health care professional.

[0196] Cancer is a type of disease that can cause almost any sign or symptom. Signs and symptoms will depend on the location of the cancer, its size, its stage, and how much it has affected nearby organs or structures. If the cancer has spread (metastasized), signs or symptoms may appear in different parts of the body.

[0197] As cancer grows, it begins to press on nearby organs, blood vessels, and nerves. This pressure causes some of the signs and symptoms of cancer. If the cancer is in a critical area, such as certain parts of the brain, even the smallest tumor can cause early symptoms that may be difficult to detect.

[0198] Sometimes cancer begins in a location and doesn't cause any symptoms until it has grown considerably larger or has reached an advanced stage. For example, pancreatic cancers usually don't grow large enough to be felt from outside the body. Some pancreatic cancers don't cause symptoms until they begin growing around nearby nerves (which can cause back pain). Others grow around the bile ducts, blocking the flow of bile and causing a yellowing of the skin called jaundice. By the time pancreatic cancer causes these signs or symptoms, it's usually in an advanced stage.

[0199] Cancer may also cause symptoms such as fever, fatigue, or unwanted weight loss. This may be because cancer cells induce a systemic proinflammatory state, consume a large portion of the body's energy supply, or release substances that alter the body's metabolism (for example, a hypermetabolic condition called cachexia), or the cancer may cause the immune system to respond in a way that produces these symptoms.

[0200] Sometimes, cancer cells release substances into the bloodstream that cause symptoms not usually attributed to the cancer. For example, some pancreatic cancers may release substances that cause blood clots to form in the leg veins. Some lung cancers produce hormone-like substances that affect calcium levels in the blood, affecting nerves and muscles and causing weakness and dizziness.

[0201] Cancer presents with several general signs and symptoms that can occur when multiple subtypes of cancer cells are present. Most people with cancer will lose weight at some time during their illness. Unexplained (unintentional) weight loss of 10 pounds or more may be the first sign of cancer, particularly pancreatic, stomach, esophageal, or lung cancer.

[0202] Fevers are common in cancer but are more common in advanced disease. Almost all people with cancer will have a fever at some time, especially if the cancer or its treatment affects the immune system and makes it harder for the body to fight infection. Less often, a fever can be an early sign of cancer, such as leukemia or lymphoma.

[0203] As cancer progresses, fatigue can be a significant symptom. It may occur early in a cancer (such as leukemia) or if the cancer causes ongoing blood loss, as in some colon or stomach cancers.

[0204] Pain can be an early symptom of some cancers, such as bone or testicular cancer. But most often, pain is a symptom of advanced disease.

[0205] In addition to skin cancer, some internal cancers can cause visible skin signs. These changes include skin that appears darker (hyperpigmentation), yellow (jaundice), or red (erythema); itching; or excessive hair growth.

[0206] Alternatively or additionally, subtypes of cancer may present with specific signs or symptoms. Changes in bowel habits or bladder function may indicate cancer. Long-term constipation, diarrhea, or changes in stool size may be signs of colon cancer. Painful urination, blood in the urine, or changes in bladder function (such as more or less frequent urination) may be associated with bladder or prostate cancer.

[0207] Changes in skin conditions or the appearance of new skin conditions may indicate cancer. Skin cancers may bleed and look like sores that won't heal. Long-lasting sores in the mouth may be oral cancer, especially in people who smoke, chew tobacco, or drink alcohol regularly. Sores on the penis or vagina may be a sign of infection or early cancer.

[0208] Unusual bleeding or discharge may indicate cancer. Unusual bleeding may occur in early-stage or advanced cancer. Blood in sputum (phlegm) may be a sign of lung cancer. Blood in the stool (or dark or black stool) may be a sign of colon or rectal cancer. Cervical cancer or cancer of the endometrium (endometrium) may cause vaginal bleeding. Blood in the urine may be a sign of bladder or kidney cancer. A bloody discharge from the nipples may be a sign of breast cancer.

[0209] Thickening or lumps in the breast or other parts of the body may indicate the presence of cancer. Many cancers can be felt through the skin, most often in the breasts, testicles, lymph nodes (glands), and soft tissues of the body. A lump or thickening can be an early or late sign of cancer. Any lump or thickening may be a sign of cancer, especially if the formation is new or has grown in size.

[0210] Indigestion or difficulty swallowing may indicate cancer. Although these symptoms often have other causes, indigestion or swallowing problems may be a sign of esophageal, stomach, or pharyngeal (throat) cancer.

[0211] Recent changes in a wart or mole may indicate cancer. Any wart, mole, or freckle that changes color, size, or shape, or loses its defined borders, indicates the potential for cancer. For example, a skin lesion could be melanoma.

[0212] A persistent cough or hoarseness may be a sign of cancer. A persistent cough may be a sign of lung cancer. Hoarseness may be a sign of cancer of the throat (voice box) or thyroid cancer.

[0213] While the signs and symptoms listed above are the more common signs and symptoms associated with cancer, there are many other signs and symptoms that are less common and not listed here. However, this disclosure contemplates and encompasses all art-recognized signs and symptoms of cancer.

[0214] Treating cancer can result in a reduction in its growth or a decrease in tumor size. A decrease in tumor size can also be referred to as "tumor regression." Preferably, after treatment, the tumor size is reduced by 5% or more relative to its size before treatment; more preferably, the tumor size is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75% or more. The size of a tumor can be measured by any reproducible means of measurement. The size of a tumor can be measured as the diameter of the tumor.

[0215] Treatment of cancer can result in a decrease in tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more relative to its pre-treatment size; more preferably, the tumor volume is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by greater than 75% or more. Tumor volume can be measured by any reproducible means of measurement.

[0216] Treatment of cancer results in a decrease in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more relative to the number before treatment; more preferably, the number of tumors is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of tumors can be measured by any reproducible measurement means. The number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0217] Treatment of cancer can result in a decrease in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more relative to the number before treatment; more preferably, the number of metastatic lesions is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measurement means. The number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

[0218] Treatment of cancer can result in an increase in the mean progression or survival time of the treated subject population compared to a population receiving only the vehicle. Preferably, the mean progression or survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. The increase in the mean progression or survival time of a population can be measured by any reproducible means. The increase in the mean progression or survival time of a population can be measured, for example, by calculating the mean progression or survival time for a population after the start of treatment with the active compound. The increase in the mean progression or survival time of a population can also be measured, for example, by calculating the mean survival time for a population after the first round of treatment with the active compound is completed.

[0219] Treating cancer can result in an increase in the average survival time of a treated subject population compared to an untreated subject population. Preferably, the average survival time is increased by more than 30 days; more preferably, more than 60 days; more preferably, more than 90 days; and most preferably, more than 120 days. The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can be measured, for example, by calculating the average survival time for a population after the start of treatment with the active compound. The increase in the average survival time of a population can also be measured, for example, by calculating the average survival time for a population after the first round of treatment with the active compound is completed.

[0220] Treatment of cancer may result in an increase in the mean progression or survival time of the treated subject population compared to a population receiving a monotherapy with a drug that is not a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the mean progression or survival time is increased by more than 30 days; more preferably, more than 60 days; more preferably, more than 90 days; and most preferably, more than 120 days. The increase in the mean progression or survival time of a population can be measured by any reproducible means. The increase in the mean progression or survival time of a population can be measured, for example, by calculating the mean progression or survival time for a population after starting treatment with an active compound. The increase in the mean progression or survival time of a population can also be measured, for example, by calculating the mean progression or survival time for a population after the first round of treatment with an active compound is completed.

[0221] Treating cancer can result in a reduction in mortality in the treated subject population compared to a population receiving only the vehicle. Treating cancer can result in a reduction in mortality in the treated subject population compared to an untreated population. Treating cancer can result in a reduction in mortality in the treated subject population compared to a population receiving a monotherapy with a drug that is not a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Preferably, the mortality rate is reduced by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%. The reduction in mortality in the treated subject population can be measured by any reproducible means. The reduction in mortality in a population can be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after the start of treatment with the active compound. The reduction in mortality in a population can also be measured, for example, by calculating the average number of disease-related deaths per unit time for the population after the first round of treatment with the active compound is completed.

[0222] Treatment of cancer can result in a reduction in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% relative to the rate before treatment; more preferably, the tumor growth rate is reduced by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. Tumor growth rate can be measured by any reproducible means of measurement. Tumor growth rate can be measured as the change in tumor diameter per unit time.

[0223] Treating cancer can result in a reduction in tumor regrowth (sometimes also referred to as progression-free survival). Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%. Tumor regrowth can be measured by any reproducible means of measurement. Tumor regrowth can be measured, for example, by measuring the increase in tumor diameter after tumor shrinkage following a previous treatment. A reduction in tumor regrowth is indicated by the absence of a tumor recurrence after treatment has ceased.

[0224] Treatment or prevention of a cell proliferative disorder can result in a decrease in the cell proliferation rate. Preferably, after treatment, the cell proliferation rate is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The cell proliferation rate can be measured by any reproducible measurement means. The cell proliferation rate can be measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0225] Treatment or prevention of a cell proliferative disorder can result in a decrease in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The proportion of proliferating cells can be measured by any reproducible measurement means. Preferably, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample. The proportion of proliferating cells can be equivalent to the mitotic index.

[0226] Treatment or prevention of a cell proliferative disorder can result in a decrease in the size of an area or zone of cell proliferation. Preferably, after treatment, the size of the area or zone of cell proliferation is reduced by at least 5% relative to its size before treatment; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The size of an area or zone of cell proliferation can be measured by any reproducible measurement means. The size of an area or zone of cell proliferation can be measured as the diameter or width of the area or zone of cell proliferation.

[0227] Treatment or prevention of a cell proliferative disorder can result in a decrease in the number or proportion of cells having an abnormal appearance or morphology. Preferably, after treatment, the number of cells having an abnormal morphology is reduced by at least 5% relative to their size before treatment; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. Abnormal cell appearance or morphology can be measured by any reproducible measurement means. Abnormal cell morphology can be measured microscopically, for example, using an inverted tissue culture microscope. Abnormal cell morphology can take the form of nuclear pleomorphism.

[0228] Treatment of cancer or a cell proliferative disorder can result in cell death, and preferably, cell death results in a reduction of at least 10% in the number of cells in a population. More preferably, cell death refers to a reduction of at least 20%; more preferably, a reduction of at least 30%; more preferably, a reduction of at least 40%; more preferably, a reduction of at least 50%; and most preferably, a reduction of at least 75%. The number of cells in a population can be measured by any reproducible means. The number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy, and light microscopy. Methods for measuring cell death are described in Li et al., Proc Natl Acad Sci US A. 100(5): 2674-8, 2003. In one aspect, cell death occurs by apoptosis.

[0229] Preferably, an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, is not significantly cytotoxic to normal cells. A therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in more than 10% of normal cells. A therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in more than 10% of normal cells.

[0230] Contacting cells with a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can selectively induce or activate cell death in cancer cells. Administering a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to a subject in need thereof can selectively induce or activate cell death (apoptosis) in cancer cells. Contacting cells with a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, can selectively induce cell death in one or more cells affected by a cell proliferative disorder. Preferably, administering a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to a subject in need thereof selectively induces cell death in one or more cells affected by a cell proliferative disorder.

[0231] The present disclosure relates to methods of treating or preventing cancer by administering a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, to a subject in need thereof, wherein administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph, or solvate thereof, results in one or more of the following: accumulation of cells in the G1 and / or S phase of the cell cycle; cytotoxicity via cell death of cancer cells without a significant amount of cell death of normal cells; anti-tumor activity in animals with a therapeutic index of at least 2; and activation of cell cycle checkpoints. As used herein, the "therapeutic index" is the maximum tolerated dose divided by the effective dose.

[0232] For use in treatment, a "therapeutically effective amount" of a compound means that amount of the compound in a formulation which, when administered (to a mammal, preferably a human) as part of a desired dosage regimen, alleviates symptoms, relieves symptoms, or slows or prevents the onset of a disease condition, according to clinically acceptable standards or cosmetic purposes for the condition or disorder being treated (e.g., at a reasonable benefit / risk ratio applicable to any medical treatment). "Therapeutically effective amount" is synonymous with "effective dose."

[0233] As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a beneficial or desired clinical outcome. For prophylactic uses, beneficial or desired outcomes include outcomes such as eliminating or reducing the risk, lessening the severity, or delaying the onset of a disease, including its biochemical, histological, and / or behavioral symptoms, and its complications and intermediate pathological phenotypes that arise during the course of the disease. For therapeutic uses, beneficial or desired outcomes include clinical outcomes such as reducing the intensity, duration, or frequency of disease attacks, as well as reducing one or more symptoms (biochemical, histological, and / or behavioral) caused by the disease, including its complications and intermediate pathological phenotypes that arise during the course of the disease, improving the quality of life of those suffering from the disease, reducing the dosage of other drugs required to treat the disease, enhancing the effect of another drug, and / or delaying the progression of the disease in the patient. An effective dose can be administered in one or more administrations. For the purposes of this disclosure, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve, directly or indirectly, a prophylactic or therapeutic treatment. As understood in the clinical setting, an effective dose of a drug, compound, or pharmaceutical composition can be achieved in conjunction with or without another drug, compound, or pharmaceutical composition. Thus, an "effective dose" may be considered in the context of administering one or more therapeutic agents, and administration of a single agent in an effective amount may be considered if a desirable result is possible or achieved in conjunction with one or more other agents. For example, an effective amount of a compound of the present disclosure for treating a proliferative disorder is an amount sufficient to treat or alleviate one or more symptoms associated with the proliferative disorder. An "effective amount" is an amount sufficient to result in one or more of the following (which may also correspond to various aspects of the present disclosure): a reduction in tumor size, a reduction in tumor volume, a reduction in the number of tumors, a reduction in metastatic lesions, an increase in survival time, a reduction in mortality, a reduction in tumor growth rate, a reduction in tumor regrowth, a reduction in the proportion of proliferating cells, or an improvement in the quality of life of patients suffering from a proliferative disorder.

[0234] For any compound, the therapeutically effective amount can be initially estimated in cell culture assays (e.g., cell culture assays of neoplastic cells) or in animal models (usually rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD 50 / ED 50Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0235] Dosage and administration are adjusted to provide adequate levels of the active agent(s) or to maintain the desired effect. When providing one or more compounds described herein to a subject, the dose of the compound(s) administered will vary depending on factors such as the subject's age, weight, height, sex, general medical condition, past medical history, disease progression, route of administration, formulation, and the like.

[0236] On the other hand, provided herein is an effective dose of a compound of the present disclosure. For example, provided herein is a method comprising administering a dosage of a compound of the present disclosure that is effective for tumor reduction. For example, the expected dose of a compound of the present disclosure in the methods described herein may include administering an independent dose of about 200 mg / days, about 80 mg / days, about 40 mg / days, about 20 mg / days, about 10 mg / days, about 5 mg / days, about 3 mg / days, about 2 mg / days, about 1 mg / days, about 0.5 mg / days, about 0.2 mg / days, about 0.05 mg / days, about 0.01 mg / days, or about 0.001 mg / days, independent of body weight.

[0237] The effective amount of the drug for reducing metabolic dysfunction, improving tumor biomarkers and / or reducing tumors in a patient can also be administered based on body weight or surface area and can be about 0.0001 mg / kg body weight to about 5 mg / kg body weight per day. For example, the expected dose can be about 0.001 to 5 mg / kg body weight per day, about 0.001 mg / kg body weight to 2 mg / kg body weight per day, about 0.001 mg / kg body weight to 0.1 mg / kg body weight per day, about 0.001 to about 0.010 mg / kg body weight per day, or about 0.007 mg / kg body weight per day, administered in single, divided, or continuous doses. These doses can be relative to the patient's body weight (in kg), body surface area (in m 2 For example, the expected dose may be approximately 1 mg / m 2 Up to approximately 100 mg / m 2 , about 5 mg / m 2 Up to approximately 25 mg / m 2 , about 5 mg / m 2 Up to approximately 100 mg / m 2 , about 5 mg / m 2 Up to approximately 15 mg / m 2, or approximately 5 mg / m 2 Up to approximately 10 mg / m 2 .

[0238] An effective amount of an agent is an amount that provides an objectively discernible improvement in a biomarker or in a tumor as indicated by a clinician or other qualified observer. For example, a delay in progression or regression of a tumor in a patient can be measured with reference to the diameter of the tumor. A decrease in the diameter of the tumor indicates regression. The absence of tumor recurrence after cessation of treatment also indicates regression. As used herein, the term "dosage effective manner" refers to the amount of active compound that produces the desired biological effect in a subject or cell.

[0239] The dosage regimen for utilizing the compound is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0240] Administration of the compounds of the present invention according to the methods of the present disclosure may be continuous or intermittent, depending, for example, on the physiological condition of the recipient, whether the purpose of administration is therapeutic or prophylactic, and other factors known to skilled practitioners. Administration of the compounds of the present invention may be substantially continuous over a preselected period of time, or may be administered in a series of spaced doses.

[0241] For repeated administration over a few hours or longer, depending on the disease, treatment continues until required disease symptoms are suppressed, or until sufficient treatment levels are reached. For example, it is expected that one to five administrations are given weekly. Other dosing regimens include every three to four days or a less frequent regimen. In some aspects, the compound of the present disclosure is administered approximately every four days, approximately every seven days, approximately every ten days, or approximately every fourteen days. In some aspects, the compound of the present disclosure is administered approximately once a week, once every two weeks, or approximately 1 to 4 times per month, depending on the duration of the reaction to drug administration. Intermittent dosing regimens with staggered doses of 2 days to 7 days or even 14 days can be used. In some aspects, treatment can start with daily administration and then be changed to weekly administration or even monthly administration. The progress of this therapy is easily monitored by conventional techniques and detection, or by measuring standard clinical chemistry.

[0242] The frequency of administration can be determined and adjusted during the course of treatment. For example, the frequency of administration can be determined and adjusted based on the type and severity of the disease to be treated, whether the agent is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the drug, and the judgment of the attending physician. Typically, the clinician will administer the compound of the present disclosure until the dosage is achieved to achieve the desired result.

[0243] Treatment can continue for a long or short period of time as needed. A suitable treatment period can be, for example, at least about one week, at least about four weeks, at least about one month, at least about six months, at least about one year, at least about two years, or irregularly. The treatment period (monotherapy or in combination with another agent) can be terminated when the desired result (e.g., tumor reduction target) is achieved. For example, when a loss of about 5% of tumor size, about 10% of tumor size, about 20% of tumor size, about 30% of tumor size, or more of tumor size has been achieved. The treatment regimen can include a correction phase, during which the compounds of the present disclosure are administered at a dose or dosing frequency sufficient to provide a reduction in tumor size, a delay in tumor growth, or a reduction in tumor growth rate, followed by a maintenance phase, during which a lower compound dose or reduced dosing frequency is administered to prevent or delay tumor regrowth.

[0244] Compounds and pharmaceutical compositions of the present disclosure

[0245] In certain aspects, modification of the active moiety is achieved through the use of a linker structured such that upon cleavage, a fragment of the linker remains attached to the active moiety. This fragment can alter any of the molecular weight, hydrophobicity, polar surface area, or charge of the active moiety, thereby producing a modified active moiety that exhibits reduced efflux from target cells compared to the unmodified active moiety. For example, coupling a MetAP2 inhibitor active moiety via a linker described herein provides a conjugate wherein, upon cleavage of the linker, an active moiety having the fragment of the linker attached thereto (the modified active moiety) is produced. The modified active moieties described herein exhibit reduced efflux from cells compared to the unmodified active moiety, resulting in the modified active moiety exhibiting superior efficacy and pharmacokinetic properties compared to the parent small molecule.

[0246] The present disclosure provides conjugates having a linker having the following structure:

[0247]

[0248] wherein, independently for each occurrence, R4 is H or C1-C6 alkyl; R5 is H or C1-C6 alkyl; R6 is C2-C6 hydroxyalkyl; Z is –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or –NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine, alanine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4, or 5; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; L is -OH, -O-succinimide, -O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, -NH2, -NH(C2-C6 hydroxyalkyl), a halogen group or a perfluoroalkyloxy group; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11is H or alkyl; W is a MetAP2 inhibitor moiety or alkyl; x is 1 to about 450; y is 1 to about 30; n is 1 to about 100; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6. In some aspects, n is 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.

[0249] In some aspects, R4 is C1-C6 alkyl. In some aspects, R4 is methyl. In some aspects, R5 is C1-C6 alkyl. In some aspects, R5 is methyl. In some aspects, R6 is 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl. In some aspects, R6 is 2-hydroxypropyl.

[0250] In some aspects, the compound has a molecular weight greater than about 100 kDa. In some aspects, the compound has a molecular weight less than about 100 kDa. In other aspects, the molecular weight is less than about 95 kDa. In other aspects, the molecular weight is less than about 90 kDa. In other aspects, the molecular weight is less than about 80 kDa. In other aspects, the molecular weight is less than about 70 kDa. In other aspects, the molecular weight is less than about 65 kDa. In other aspects, the molecular weight is less than about 60 kDa. In other aspects, the molecular weight is less than about 45 kDa. In other aspects, the molecular weight is less than about 35 kDa.

[0251] In some aspects, the ratio of x to y is from about 100:1 to about 1:1. In some aspects, the ratio of x to y is from about 30:1 to about 3:1. In other aspects, the ratio of x to y is from about 19:2 to about 7:2. In some aspects, the ratio of x to y is from about 9:1 to about 4:1. In some aspects, the ratio of x to y is about 11:1. In some aspects, the ratio of x to y is about 9:1. In some aspects, the ratio of x to y is about 4:1. In some aspects, the ratio of x to y is about 12:1. For example, in some aspects, the x:y ratio is about 3:1; the x:y ratio is about 4:1; the x:y ratio is about 5:1; the x:y ratio is about 6:1; the x:y ratio is about 7:1; the x:y ratio is about 8:1; the x:y ratio is about 9:1; the x:y ratio is about 10:1; the x:y ratio is about 11:1; the x:y ratio is about 12:1; the x:y ratio is about 13:1; the x:y ratio is about 14:1; the x:y ratio is about 15:1; the x:y ratio is about 16:1 ; an x:y ratio of approximately 17:1; an x:y ratio of approximately 18:1; an x:y ratio of approximately 19:1; an x:y ratio of approximately 20:1; an x:y ratio of approximately 21:1; an x:y ratio of approximately 22:1; an x:y ratio of approximately 23:1; an x:y ratio of approximately 24:1; an x:y ratio of approximately 25:1; an x:y ratio of approximately 26:1; an x:y ratio of approximately 27:1; an x:y ratio of approximately 28:1; an x:y ratio of approximately 29:1; or an x:y ratio of approximately 30:1.

[0252] In certain aspects, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L. In certain aspects, L is methoxy, ethoxy, pentafluorophenoxy, phenoxy, acetoxy, fluoro, chloro, methoxycarbonyloxy, ethoxycarbonyloxy, phenoxycarbonyloxy, 4-nitrophenoxy, trifluoromethoxy, pentafluoroethoxy, or trifluoroethoxy. In certain aspects, L is 4-nitrophenoxy.

[0253] In certain aspects, Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W. In certain aspects, AA1 is glycine. In certain aspects, AA2 is glycine. In certain aspects, AA3 is glycine. In certain aspects, AA4 is glycine or phenylalanine. In certain aspects, AA5 is leucine, phenylalanine, valine, or tyrosine. In certain aspects, AA6 is asparagine, citrulline, glutamine, glycine, leucine, methionine, threonine, or tyrosine. In some aspects, AA5-AA6 are Leu-Cit, Leu-Gln, Leu-Gly, Leu-Leu, Leu-Met, Leu-Thr, Phe-Cit, Phe-Gln, Phe-Leu, Phe-Met, Phe-Thr, Val-Asn, Val-Cit, Val-Gln, Val-Leu, Val-Met, Val-Thr, Tyr-Cit, Tyr-Leu, or Tyr-Met. In some aspects, AA1, AA3, and AA5 are glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine. In some aspects, AA2, AA4, and AA6 are glycine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, threonine, or tyrosine. In some aspects, AA2 is a bond; and AA3 is a bond. In certain aspects, AA1 is glycine; AA4 is phenylalanine; AA5 is leucine; and AA6 is glycine.

[0254] In some ways, W is

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] wherein R2 is –OH or methoxy; and R3 is H, –OH or methoxy.

[0262] In some ways, W is

[0263]

[0264] .

[0265] In some ways, W is .

[0266] In some aspects, Q is NR. In other aspects, Q is S.

[0267] In certain aspects, J is NR. In other aspects, J is ((CH2) q Q) r In other aspects, J is C5-C8 cycloalkyl. In certain aspects, J is aryl.

[0268] In certain aspects, Y is NR. In other aspects, Y is S.

[0269] In some ways, -QXY- is

[0270]

[0271]

[0272] V is:

[0273]

[0274] or key; R 12 is H or Me; or R 12 With R 14 Together they form a piperidine ring; R 11 is H or Me; and R 13 With R 12 Together they form a piperidine ring.

[0275] In some ways, -QXY- is .

[0276] In some ways, –QXY- is .

[0277] In some ways, –QXY- is .

[0278] In some ways, -QXY is .

[0279] In some ways, –QXY- is In some ways, -QXY- is .

[0280] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0281] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0282] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0283] In certain aspects, R4 and R5 are methyl; R6 is 2-hydroxypropyl; Z is -NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-QXYC(O)-W; AA1 is glycine; AA2 is a bond; AA3 is a bond; AA4 is phenylalanine; AA5 is leucine; AA6 is glycine; -QXY- is ; and W is .

[0284] In certain aspects, -QXY- is a self-immolating linker that releases the MetAP2 inhibitor as a carbamate derivative, as shown in the following scheme:

[0285]

[0286] Another aspect of the present disclosure provides a conjugate having a linker having the following structure: ZQXYC(O)-W; wherein, independently for each occurrence, Z is H2N-AA2-AA3-AA4-AA5-AA6-C(O)- or H; AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; , proline, glutamine, arginine, serine, threonine, valine, tryptophan or tyrosine; AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan or tyrosine; AA5 is a bond, alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan or; AA6 is alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine or H2N(CH2) m CO2H, wherein m is 2, 3, 4 or 5; Q is NR, O or S; X is M-(C(R)2) p -MJM-(C(R)2) p -MV; M is a bond, or C(O); J is a bond, or ((CH2) q Q) r , C5-C8 cycloalkyl, aryl, heteroaryl, NR, O or S; Y is NR, O or S; R is H or alkyl; V is a bond or ; R 9 is alkyl, aryl, aralkyl or a bond; or R 9 Together with Y, it forms a heterocyclic ring; R 10 is an amide group or a bond; R 11 is H or alkyl; W is a MetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6.

[0287] In some aspects, Z is H2N-AA5-AA6-C(O)-. In some aspects, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine, and AA6 is glycine. In some aspects, AA5 is leucine, and AA6 is glycine. In some aspects, AA5 is valine, and AA6 is glycine. In some aspects, AA5 is phenylalanine, and AA6 is glycine. In some aspects, AA5 is glycine, and AA6 is glycine. In some aspects, AA5 is not valine.

[0288] In other aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-. In certain aspects, AA5 is alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, valine, tryptophan, or tyrosine, and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA5 is leucine, and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA5 is valine, and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA5 is phenylalanine, and each of AA3, AA4, or AA6 is glycine. In certain aspects, AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine. In certain aspects, each of AA3, AA4, AA5, and AA6 is glycine. In certain aspects, AA5 is not valine.

[0289] In certain aspects, Z is H. In other aspects, Z is H2N-AA6-C(O)-. In certain aspects, AA6 is glycine.

[0290] In certain aspects, Q is NR. In certain aspects, M is a bond. In certain aspects, J is a bond. In certain aspects, Y is NR.

[0291] In some ways, W is:

[0292]

[0293]

[0294]

[0295]

[0296]

[0297] wherein R2 is –OH or methoxy; and R3 is H, –OH or methoxy.

[0298] In some ways, W is

[0299]

[0300] .

[0301] In some ways, W is .

[0302] In some ways, -QXY- is

[0303]

[0304]

[0305] V is:

[0306]

[0307]

[0308] or key; R 12 is H or Me; or R 12 With R 14 Together they form a piperidine ring; R 11 is H or Me; and R 13 With R 12 Together they form a piperidine ring.

[0309] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0310] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine, and AA6 is glycine; QXY is ; and W is .

[0311] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine, and AA6 is glycine; QXY is ; and W is .

[0312] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine, and AA6 is glycine; QXY is ; and W is .

[0313] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0314] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0315] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0316] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0317] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0318] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0319] In some ways, Z is H; QXY is ; And W is .

[0320] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0321] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine, and AA6 is glycine; QXY is ; and W is .

[0322] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine, and AA6 is glycine; QXY is ; and W is .

[0323] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine, and AA6 is glycine; QXY is ; and W is .

[0324] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0325] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0326] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0327] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0328] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0329] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0330] In some ways, Z is H; QXY is ; and W is .

[0331] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0332] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine, and AA6 is glycine; QXY is ; and W is .

[0333] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine, and AA6 is glycine; QXY is ; and W is .

[0334] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine, and AA6 is glycine; QXY is ; and W is .

[0335] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0336] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0337] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0338] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0339] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0340] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0341] In some ways, Z is H; QXY is ; And W is .

[0342] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0343] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is valine, and AA6 is glycine; QXY is ; and W is .

[0344] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is phenylalanine, and AA6 is glycine; QXY is ; and W is .

[0345] In certain aspects, Z is H2N-AA5-AA6-C(O)-; AA5 is glycine, and AA6 is glycine; QXY is ; and W is .

[0346] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is leucine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0347] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is valine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0348] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA5 is phenylalanine, and each of AA3, AA4, or AA6 is glycine; QXY is ; and W is .

[0349] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; AA3 is glycine, AA4 is phenylalanine, AA5 is leucine, and AA6 is glycine; QXY is ; and W is .

[0350] In certain aspects, Z is H2N-AA3-AA4-AA5-AA6-C(O)-; each of AA3, AA4, AA5, and AA6 is glycine; QXY is ; and W is .

[0351] In certain aspects, Z is H2N-AA6-C(O)-; AA6 is glycine; QXY is ; and W is .

[0352] In some ways, Z is H; QXY is ; And W is .

[0353] Other active moieties that can be modified for use in the conjugates of the present disclosure include the following structures:

[0354]

[0355] .

[0356] In certain aspects, the active moiety is an anti-tumor compound. In other aspects, the active moiety is a molecule that inhibits methionine aminopeptidase-2 (MetAP2), such as fumagillin, fumagillol, or an analog, derivative, salt, or ester thereof. MetAP2 is a co-translational enzyme responsible for cleaving the initiator methionine from nascent polypeptides. It has several unique substrates and is often upregulated under conditions of cellular stress, hypoxia, and during cell division. Fumagillin is a natural product derived from the biomass of the fungus Aspergillus fumigatus Fresenius. Fumagillin and its analogs and derivatives are known to inhibit the aminopeptidase activity of MetAP2. Other exemplary MetAP2 inhibitors are described in U.S. Patent Nos. 6,242,494 to Craig et al., 6,063,812 to Hong et al., 6,887,863 to Craig et al., 7,030,262 to BaMaung et al., 7,491,718 to Comess et al., and patent application WO2017027684, each of which is incorporated herein by reference in its entirety. Additional exemplary MetAP2 inhibitors are described in Wang et al., “Correlation of tumor growth suppression and methionine aminopeptidase-2 activity blockade using an orally active inhibitor,” PNAS 105(6) 1838-1843(2008); Lee et al. "Design, Synthesis, and Antiangiogenic Effects of a Series ofPotent Novel Fumagillin Analogues", Chem. Pharm. Bull. 55(7) 1024-1029(2007); Jeong et al. "Total synthesis and antiangiogenic activity of cyclopentaneanalogues of fumagillol", Bioorganic and Medicinal Chemistry Letters 15, 3580-3583 (2005); Arico-Muendel et al. "Carbamate Analogues of Fumagillin as Potent, Targeted Inhibitors of Methionine Aminopeptidase-2", J. Med. Chem.52, 8047-8056 (2009); and in International Publication No. WO 2010 / 003475 to Heinrich et al.

[0357] Fumagillin is a small molecule that has been used as an antimicrobial and antiprotozoal agent. Its physicochemical properties and production methods are well known (see U.S. Pat. No. 2,803,586 and Turner, JR et al., The Stereochemistry of Fumagillin, Proc. Natl. Acad. Sci. 48 , 733-735 (1962). The fermentation product fumagillin can be hydrolyzed to produce the alcohol fumagillol, which in turn can be converted to various derivatives, including carbamoylfumagillol MW 325. The synthesis and preparation of carbamoylfumagillol and some small molecule derivatives are described in U.S. Patent No. 5,166,172.

[0358] Fumagillin and related compounds are believed to exert their biological effects by inhibiting MetAP2, an enzyme that removes N-terminal methionine from nascent cellular proteins (see Tucker, LA et al., “Ectopic Expression of Methionine Aminopeptidase-2 Causes Cell Transformation and Stimulates Proliferation”, Oncogene 27, 3967 (2008)).

[0359] Carbamoyl fumagillin and derivatives, as well as other inhibitors of MetAP2, have shown therapeutic benefit in preclinical and clinical studies. As described in U.S. Patent No. 5,166,172, these compounds inhibit cell proliferation and angiogenesis. Fumagillin analogs or derivatives, such as CKD-732 and PPI-2458, have been extensively studied in various systems, as detailed by Bernier et al. in "Fumagillin class inhibitors of methionineaminopeptidase-2," Drugs of the Future 30(5): 497-508, 2005.

[0360] The anti-obesity effects of fumagillin and its analogs are well known. Rupnick et al., "Adipose tissue mass can be regulated through the vasculature," PNAS 99, 10730-10735, 2002, describe weight loss in ob / ob mice at daily doses of TNP-470 ranging from 2.5 mg / kg to 10 mg / kg. Brakenhielm describes the prevention of obesity with TNP-470 doses of 15 or 20 mg / kg every other day ("The Angiogenesis Inhibitor, TNP-470, Prevents Diet-Induced and Genetic Obesity in Mice," Circulation Research 94: 1579-1588, 2004). Kim et al., “Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732” J Molecular Endocrinology 38, 455-465, 2007, describe weight loss in C57BL / 6J mice and SD rats at a dose of 5 mg / kg / day. Lijnen et al., “Fumagillin reduces adipose tissue formation in murine models of nutritionally induced obesity” Hughes et al. (Obesity 12, 2241-2246, 2010) describe weight loss in C57BL / 6 mice after oral delivery of 1 mg / kg of fumagillin per day.

[0361] One of these derivatives, chloroacetylcarbamoylfumagillol (TNP-470), has been extensively studied (see H. Mann-Steinberg et al., "TNP-470: The Resurrection of the First Synthetic Angiogenesis Inhibitor," Chapter 35, in Folkman and Figg, Angiogenesis: An Integrative Approach from Science to Medicine, Springer NY (2008)). TNP-470 has shown activity against a number of cancers, including lung, cervical, ovarian, breast, and colon cancers. Due to dose-limiting neurotoxicity, TNP-470 has been tested using multiple dosing regimens, but attempts to limit its toxicity have been unsuccessful. Consequently, TNP-470 has been found to be too toxic to be suitable for human use. TNP-470 has a short half-life and requires prolonged intravenous administration for therapeutic use. The metabolite of TNP-470, carbamoyl fumagillol, has a half-life of 12 minutes in humans (see Herbst et al., “Safety and Pharmacokinetic Effects of TNP-470, an Angiogenesis Inhibitor, Combined with Paclitaxel in Patients with Solid Tumors: Evidence for Activity in Non-Small-Cell Lung Cancer”, Journal of Clinical Oncology 20(22) 4440-4447 (2002). In addition, fumagillin and its derivatives are hydrophobic and difficult to formulate.

[0362] Despite the known usefulness of fumagillin derivatives, they have not been successfully used therapeutically due to the inability to overcome the low water solubility, short half-life values, and neurotoxic side effects of these compounds. Based on previously observed dose-limiting neuropsychiatric toxicity, the combination of TNP-470 and paclitaxel has been identified as having a 60 mg / m2 dose three times a week. 2The MTD of CKD-732 was 15 mg / m² administered every four days due to confusion and insomnia. 2 Therefore, the compounds of the present disclosure are more effective, exhibit reduced toxicity (lower neurotoxicity), improved water solubility, are more stable, and / or have a longer half-life (serum half-life) than currently known fumagillin derivatives.

[0363] As used herein, the phrase "reduced toxicity" has its ordinary meaning as understood by those skilled in the art. By way of example only, and in no way as a limitation of the meaning of the term, administration of a fumagillin analog conjugate resulted in fewer side effects in an open field test in mice compared to a fumagillin analog alone.

[0364] The phrase "improved water solubility" has its ordinary meaning as understood by those skilled in the art. By way of example only, and in no way as a limitation of the meaning of this term, the following description of this term is meaningful: an increased amount of the fumagillin analog will be soluble in water due to its covalent incorporation into the conjugate, compared to the amount of the unconjugated fumagillin analog that is soluble in water alone.

[0365] The phrase "longer half-life" has its ordinary meaning as understood by those skilled in the art. By way of example only, and in no way as a limitation on the meaning of this term, the following description of this term is meaningful: any significant increase in the length of time required to inactivate a fumagillin conjugate in vivo or in vitro compared to the half-life of the fumagillin analog alone in vivo or in vitro.

[0366] Without being bound by theory, non-enzymatic inhibition of extracellular signal-regulated kinases 1 and 2 (ERK1 / 2) by MetAP2 may be important, as may binding of the eukaryotic initiation factor (eIF) by MetAP2. Cellular responses to MetAP2 inhibition, reflecting potential ERK-related processes, may include inhibition of sterol regulatory element-binding protein (SREBP) activity, leading to reduced lipid and cholesterol biosynthesis. Interestingly, altered gene expression patterns in liver and adipose tissue following prolonged (approximately 9 months) fumagillin exposure suggest that MetAP2 inhibition may also alter the relative abundance of factors involved in inflammation, consistent with reduced ERK-dependent cellular processes. The proposed mechanism by which MetAP2 inhibition leads to the shift in fat accumulation and the catabolism of free fatty acids, which serve as a source of body energy, is supported by changes in plasma β-hydroxybutyrate, adiponectin, leptin, and FGF21 observed in a previous study (Hughes et al., Obesity (2013) 21, 9, 1782-1788). Elevated levels of the key catabolic hormones adiponectin and FGF21, along with the appearance of ketone bodies (β-hydroxybutyrate), suggest that MetAP2 inhibition using the disclosed compounds—conjugated or modified fumagillin, fumagillol, or their analogs, derivatives, salts, or esters—stimulates energy expenditure, fat utilization, and lipid excretion. The reduction in leptin observed in previous studies and the studies presented herein is also consistent with a reduction in total adipose tissue and a negative energy balance. The disclosed compounds—conjugated or modified fumagillin, fumagillol, or their analogs, derivatives, salts, or esters—may also form a covalent bond with MetAP2, thereby irreversibly inhibiting and silencing the existing enzyme until a newly generated pool of MetAP2 is generated in target tissues (e.g., liver and adipose tissue).

[0367] In certain aspects, the compounds of the present disclosure: conjugated or modified fumagillin, fumagillol, or an analog, derivative, salt, or ester thereof, for example, have the following structural formula as shown in Table 1:

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394] *Where the polymer has the following structure:

[0395]

[0396] And preferably has the following structure:

[0397] .

[0398] In some aspects, the compound is:

[0399] (Compound 1).

[0400] In some aspects, the compound is:

[0401] (Compound 2).

[0402] In some aspects, the compound is:

[0403] (Compound 3).

[0404] In some aspects, the compound is:

[0405] .

[0406] In some aspects, the compound is:

[0407] .

[0408] In some aspects, the compound is:

[0409] .

[0410] In one or more aspects, the compounds for use in the present disclosure can be selected from cis-(3aRS,9bRS)-7-(phenylsulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorophenylsulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorophenylsulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aRS,9bRS)-7-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aR,9bR)-7-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; cis-(3aS,9bS)-7-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid Formic acid; 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid, formate; 7-(benzenesulfonylamino)-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylic acid, formate; cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a, 2,7b-Tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((E)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; cis-(3aRS,9bRS)-7-[2-(4-Dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid; (1aR,7bS)-5-[2-(3-Diethylaminopropyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z )-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-Ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid 1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid 1a,2,7b-Tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2[(Z)-3-(Pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-{2[(Z)-3-(Pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(3-Dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aR,7bS)-5-[2-(3-Dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2-(3-Dimethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-Dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-(4-Dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid Formic acid; (1aS,7bR)-5-[2-(4-dimethylaminobutylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(5-dimethylaminopentylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl] ]-4-Fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid 1a,2,7b-Tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-1-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azetidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; N-(4-Dimethylaminobutyl)-N-methylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)-methyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)-methyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid 1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-(Pyrrolidin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid 2,7b-Tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)carbonyl-aminomethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((S)-1-Ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(3-Dimethylaminopropylcarbamoyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[N-((S)-1-Ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid Acid; (1aRS, 7bSR) -5-(2-{[N-((R)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-phenylsulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS, 7bSR) -5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]-phenylsulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS, 7bSR) -5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethylamino]-phenylsulfonylamino}-1,1a,2,7b -tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(3-N,N,-diethylaminopropylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidin-2-yl)carbonylamino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid Chromene-4-carboxylic acid; (1aS,7bR)-5-[2-((Z)-3-Diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((Z)-3-Diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{N-[((R)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidin-2-yl)carbonyl]-N-methylamino-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2 -[((S)-1-Ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid -amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-Azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-Azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1, 1a,2,7b-Tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl)}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid -carboxylic acid; (1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; ,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; (1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropane[c]chromene-4-carboxylic acid; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

[0411] In one or more aspects, the compound is selected from:

[0412]

[0413]

[0414] and pharmaceutically acceptable salts or stereoisomers thereof.

[0415] For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Edition, 1986-87, inside cover.

[0416] The term "alkyl" refers to a fully saturated branched or unbranched carbon chain radical having the specified number of carbon atoms, or up to 30 carbon atoms if no specification is made. For example, "lower alkyl" refers to an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those that are positional isomers of these alkyl groups. Alkyl groups having 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain aspects, a straight or branched alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C1-C2 for a straight chain). 30 , for the branched chain C3-C 30 ), and more preferably 20 or fewer carbon atoms. Likewise, some cycloalkyls have 3-10 carbon atoms in their ring structure, and may have 5, 6, or 7 carbon atoms in the ring structure.

[0417] Unless otherwise specified carbon number, "lower alkyl" as used herein refers to an alkyl group as defined above, but having 1 to 10 carbons, or 1 to 6 carbon atoms in its backbone structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, some alkyl groups are lower alkyl groups. In some aspects, the substituents designated as alkyl herein are lower alkyl groups.

[0418] As used herein, the term "carbocycle" refers to an aromatic or non-aromatic ring in which every atom of the ring is carbon.

[0419] As used herein, the term "aryl" includes 5-, 6-, and 7-membered monocyclic aromatic groups that may contain from zero to four heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatic groups." The aromatic ring may be substituted at one or more ring positions with such substituents as described above, such as halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonic acid / phosphonate, phosphinic acid / phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic radical, aromatic or heteroaromatic moiety, -CF , -CN, etc. The term "aryl" also includes polycyclic ring systems having two or more rings in which two or more carbon atoms are common to two adjacent rings (such rings are "fused rings"), wherein at least one ring is aromatic, e.g., the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl.

[0420] "Alkenyl" refers to any branched or unbranched unsaturated carbon chain radical having the specified number of carbon atoms, or up to 26 carbon atoms if no limitation is specified, and having one or more double bonds in the radical. Examples of alkenyl radicals of 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, wherein the unsaturated bond(s) may be located anywhere in the radical and may have the (Z) or (E) configuration around the double bond(s).

[0421] The term "alkynyl" refers to a hydrocarbon group within the scope of an alkenyl group, but having one or more triple bonds within the group.

[0422] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined below having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, the substituent of an alkyl group that makes an alkyl group an ether is an alkoxy group or an alkoxy-like group, such as -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) m -R1, where m and R1 are described below.

[0423] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 10-membered ring structure, more preferably a 3- to 7-membered ring, which ring structure includes one to four heteroatoms. The heterocycle can also be polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidones, sultams, sultones, and the like. The heterocycle can be substituted at one or more positions with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonic acid, phosphonate, phosphinic acid, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0424] The term "alkylthio" refers to an alkyl group as defined above having a thio group attached thereto. In certain aspects, the "alkylthio" moiety consists of -(S)-alkyl, -(S)-alkenyl, -(S)-alkynyl, and -(S)-(CH2) m wherein m and R1 are as defined below. Representative alkylthio groups include methylthio, ethylthio, and the like.

[0425] As used herein, the term "nitro" refers to -NO2; the term "halogen" means F, Cl, Br or I; the term "mercapto" refers to -SH; the term "hydroxy" refers to -OH; and the term "sulfonyl" refers to -SO2-.

[0426] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines, for example, moieties that can be represented by the following general formula:

[0427]

[0428] wherein R3, R5 and R6 each independently represent hydrogen, alkyl, alkenyl, -(CH2) m-R1, or R3 and R5 taken together with the nitrogen atom to which they are attached complete a heterocyclic ring having 4 to 8 atoms in the ring structure; R1 represents an alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl; and m is zero or an integer from 1 to 8. In certain aspects, only one of R3 or R5 can be a carbonyl group, for example, R3, R5, and nitrogen together do not form an imide. In certain aspects, R3 and R5 (and optionally R6) each independently represent hydrogen, alkyl, alkenyl, or -(CH2) m -R1. Thus, the term "alkylamine" as used herein refers to an amine group as defined above having a substituted or unsubstituted alkyl group attached thereto, i.e., at least one of R3 and R5 is an alkyl group. In certain aspects, the amino group or alkylamine is basic, meaning that it has a pK a > 7.00. The protonated forms of these functional groups have pK relative to water greater than 7.00 a .

[0429] The term "carbonyl" (C(O)) is art-recognized and includes moieties that can be represented by the following general formula:

[0430]

[0431] wherein X is a bond or represents oxygen or sulfur, and R7 represents hydrogen, alkyl, alkenyl, -(CH2) m -R1 or a pharmaceutically acceptable salt, R8 represents hydrogen, alkyl, alkenyl or -(CH2) m -R1, wherein m and R1 are as defined above. When X is oxygen and R7 or R8 are not hydrogen, the formula represents an "ester". When X is oxygen and R7 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R7 is hydrogen, the formula represents a "carboxylic acid". When X is oxygen and R8 is hydrogen, the formula represents a "formates". Typically, when the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. When X is sulfur and R7 or R8 is not hydrogen, the formula represents a "thioester" group. When X is sulfur and R7 is hydrogen, the formula represents a "thiocarboxylic acid" group. When X is sulfur and R8 is hydrogen, the formula represents a "thioformate" group. On the other hand, when X is a bond and R7 is not hydrogen, the above formula represents a "ketone" group. When X is a bond and R7 is hydrogen, the above formula represents an "aldehyde" group.

[0432] The term "substituted" as used herein is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above herein. For appropriate organic compounds, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein (which satisfy the valence of the heteroatoms). This disclosure is not intended to be limited in any way by the permissible substituents of organic compounds. It is to be understood that "substituted" or "substituted with..." includes implicit restrictions, i.e., such substitutions are based on the permissible valences of the substituted atoms and substituents, and the substitution results in a stable compound, such as a compound that does not spontaneously undergo a transformation such as that caused by rearrangement, cyclization, elimination, etc.

[0433] The term "sulfamoyl" is art-recognized and includes moieties that can be represented by the following general formula:

[0434]

[0435] wherein R3 and R5 are as defined above.

[0436] The term "sulfate" is art-recognized and includes moieties that can be represented by the following general formula:

[0437]

[0438] wherein R7 is as defined above.

[0439] The term "sulfonylamino" is art-recognized and includes moieties that can be represented by the following general formula:

[0440]

[0441] wherein R2 and R4 are as defined above.

[0442] The term "sulfonic acid / sulfonate group" is art-recognized and includes moieties that can be represented by the following general formula:

[0443]

[0444] wherein R7 is an electron pair, hydrogen, alkyl, cycloalkyl or aryl.

[0445] As used herein, the term "sulfoxide" or "sulfinyl" refers to a moiety that can be represented by the following general formula:

[0446]

[0447] where R 12 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl or aryl.

[0448] Similar substitutions may be made on alkenyl and alkynyl groups to produce, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl groups.

[0449] As used herein, the definition of each expression, such as alkyl, m, n, etc., when it occurs more than one time in any structure is intended to be independent of its definition elsewhere in the same structure.

[0450] The term "amino acid" is intended to encompass all compounds, whether natural or synthetic, that include both an amino and an acid function, including amino acid analogs and derivatives. In certain aspects, the amino acids contemplated in the present disclosure are those naturally occurring amino acids found in proteins, or naturally occurring anabolic or catabolic products of such amino acids, which contain an amino and a carboxyl group. Naturally occurring amino acids are identified by traditional three-letter and / or one-letter abbreviations corresponding to the common names of the amino acids according to the following list. The abbreviations are accepted in the peptide field and recommended by the IUPAC-IUB Committee on Biochemical Nomenclature.

[0451] The term "amino acid residue" refers to an amino acid. Generally, the abbreviations used herein to designate naturally occurring amino acids are based on the recommendations of the IUPAC-IUB Committee on Biochemical Nomenclature (see Biochemistry (1972) 11: 1726-1732). For example, Met, Ile, Leu, Ala, and Gly represent the "residues" of methionine, isoleucine, leucine, alanine, and glycine, respectively. A residue refers to a group derived from the corresponding α-amino acid by eliminating the OH portion of the carboxyl group and the H portion of the α-amino group.

[0452] The term "amino acid side chain" is the portion of an amino acid residue that is not bound to the main chain, as defined in KD Kopple, "Peptides and Amino Acids", WA Benjamin Inc., New York and Amsterdam, 1966, pp. 2 and 33; examples of side chains of such common amino acids are -CH2CH2SCH3 (the side chain of methionine), -CH2(CH3)-CH2CH3 (the side chain of isoleucine), -CH2CH(CH3)2 (the side chain of leucine), or H- (the side chain of glycine). These side chains are attached to the main chain Cα carbon.

[0453] As used herein, the term "peptide" refers to a sequence of amino acid residues linked together by peptide bonds or modified peptide bonds. The term "peptide" is intended to encompass peptide analogs, peptide derivatives, peptidomimetics, and peptide variants. The term "peptide" is understood to include peptides of any length. The peptide sequences listed herein are written according to generally accepted conventions, with the N-terminal amino acid on the left and the C-terminal amino acid on the right (e.g., H2N-AA1-AA2-AA3-AA4-AA5-AA6-CO2H).

[0454] Certain compounds of the present disclosure may exist in particular geometric isomers or stereoisomers. The present disclosure contemplates all such compounds falling within the scope of the present disclosure, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present disclosure. Any representation of a particular isomer is merely exemplary (e.g., the example of a trans-isomer also encompasses a cis-isomer).

[0455] For example, if a specific enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), 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 the pure enantiomers are then recovered.

[0456] As used herein, the term "substituted" refers to the replacement of any one or more hydrogen atoms on a designated atom by a selected indicated group, provided that the normal valence of the designated atom is not exceeded and that the replacement results in a stable compound. When the substituent is a keto group (i.e., =0), then two hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are intended to indicate a compound that is robust enough to withstand isolation from a reaction mixture to a usable purity and formulation into an effective therapeutic agent.

[0457] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0458] When any variable (e.g., R1) occurs more than once in any constituent or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown as substituted with 0-2 R1 moieties, that group can be optionally substituted with up to two R1 moieties, and each occurrence of R1 is independently selected from the definition of R1. Likewise, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0459] In this specification, in some cases, for convenience, the structural formula of a compound represents certain isomers, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, etc. In addition, the compound represented by the structural formula may exist in crystal polymorphism. It should be noted that any crystal form, crystal form mixture, or its anhydride or hydrate is included in the scope of this disclosure. In addition, so-called metabolites produced by the in vivo degradation of the present compound are included in the scope of this disclosure.

[0460] "Isomeries" refers to compounds that have the same molecular formula but differ in the sequence in which their atoms are bonded or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of enantiomeric forms of opposite chirality is called a "racemic mixture."

[0461] A carbon atom bonded to four different substituents is called a "chiral center."

[0462] "Chiral isomer" refers to a compound with at least one chiral center. Compounds with more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers (called a "diastereomeric mixture"). When one chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents contemplated for attachment to the chiral center are based on the method of Cahn, Ingold and Prelog. Sequence Rule to arrange. (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).

[0463] "Geometric isomers" refer to diastereomers that exist due to hindered rotation about a double bond. The names of these configurations are distinguished by the prefixes cis and trans, or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0464] In addition, the structures and other compounds discussed in this disclosure include all atropisomers thereof. "Atropisomers" are a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. Atropisomers exist due to restricted rotation caused by the hindered rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, but due to recent advances in chromatographic techniques, it is possible to separate mixtures of two atropisomers under selected circumstances.

[0465] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the migration of hydrogen atoms and is accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer sets in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization can occur, a chemical equilibrium of the tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers being interconvertible through tautomerization is called tautomerism.

[0466] Of the various possible types of tautomerism, two are common. In keto-enol tautomerism, a simultaneous transfer of electrons and hydrogen atoms occurs. Ring-chain tautomerism is caused by the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, causing it to assume a cyclic (ring-shaped) form, as shown by glucose.

[0467] Common tautomeric pairs are: keto-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocycles (e.g. in nucleic acid bases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine.

[0468] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It is also to be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form.

[0469] The terms "crystal polymorph," "polymorph," or "crystalline form" refer to a crystal structure in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all having the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0470] In addition, the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

[0471] "Solvate" refers to a solvent-adducted form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an 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, where the water retains its molecular form, HO.

[0472] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another compound but slightly different in composition (e.g., the replacement of an atom by an atom of a different element or the presence of a particular functional group, or the replacement of one functional group by another). Thus, an analog is a compound that is similar or comparable in function and appearance, but differs from the reference compound in structure or origin.

[0473] The term "derivative" as defined herein refers to compounds having a common core structure and substituted with various groups as described herein.

[0474] The term "bioisostere" refers to a compound produced by exchanging an atom or group of atoms for another substantially similar atom or group of atoms. The purpose of bioisosteric substitution is to create new compounds with similar biological properties as the parent compound. Bioisosteric substitution can be physicochemical or topological. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0475] The present disclosure is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0476] The synthetic methods disclosed herein can accommodate a wide variety of functional groups; therefore, a variety of substituted starting materials can be used. The methods generally provide the desired final compound at or near the end of the overall process, although in some cases it may be desirable to further convert the compound into a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0477] The compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures known to those skilled in the art or apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Although not limited to any one or more sources, classic textbooks such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 5th ed., John Wiley & Sons:New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis , 3rd edition, John Wiley & Sons: New York, 1999 (incorporated herein by reference) is a useful and recognized reference textbook on organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are intended to illustrate but not to limit the general procedures for preparing the compounds of the present disclosure.

[0478] In particular, the compounds of the present disclosure and their synthesis are further described in PCT Publication Nos. WO 2011 / 150022 and WO 2011 / 150088 and US Pat. Nos. 9,173,956, 9,320,805 and 9,433,600. Each of these publications is hereby incorporated by reference in its entirety for all purposes.

[0479] The present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0480] A "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one aspect, the pharmaceutical composition is in bulk or unit dosage form. A unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps on an aerosol inhaler, or vials. The amount of active ingredient (e.g., a formulation of a disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will appreciate that it is sometimes necessary to routinely vary the dosage based on the patient's age and condition. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the disclosed compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one aspect, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any needed preservatives, buffers, or propellants.

[0481] As used herein, "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference textbook in this field. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.

[0482] Pharmaceutically acceptable carriers include solid carriers such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers include syrup, peanut oil, olive oil, water, and the like. Similarly, the carrier or diluent can include time-delay materials known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with wax, ethylcellulose, hydroxypropyl methylcellulose, methyl methacrylate, and the like. Other fillers, excipients, flavorings, and other additives known in the art may also be included in the pharmaceutical composition according to the present disclosure. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents to date are incompatible with the active compound, their use in the composition is contemplated. Supplementary active compounds may also be incorporated into the composition. In certain aspects, the pharmaceutical composition comprises DMSO.

[0483] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by reacting the purified compound(s) in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, and laurylsulfonate, among others. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, among others. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0484] As used herein, the phrase "pharmaceutically acceptable" refers to those ligands, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, are substantially non-pyrogenic, and do not cause excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0485] As used herein, the term "metabolite" refers to a metabolic product of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof, that exhibits similar in vivo activity as the compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, diastereomer, and polymorph thereof.

[0486] As used herein, the term "prodrug" refers to a compound of the present invention or its pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs covalently linked to one or more promoieties, such as an amino acid moiety or other water-soluble moiety. The compound of the present invention or its pharmaceutically acceptable salts, solvates, diastereomers, and polymorphs can be released from the promoieties via hydrolysis, oxidation, and / or enzymatic release mechanisms. On the one hand, the prodrug compositions of the present invention exhibit the additional benefits of increased water solubility, improved stability, and improved pharmacokinetic properties. The promoieties can be selected to obtain desired prodrug characteristics. For example, the promoieties (e.g., amino acid moieties or other water-soluble moieties, such as phosphates in R4) can be selected based on solubility, stability, bioavailability, and / or in vivo delivery or absorption. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyl functional groups in the compounds of the present disclosure, esters (e.g., ethyl ester, morpholinoethanol ester), N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases, and enaminones of amino functional groups, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups, and the like, see Bundegaard, H., et al. Design of Prodrugs , pp. 1–92, Elesevier, New York-Oxford (1985).

[0487] The compounds of the present invention, or pharmaceutically acceptable salts, esters, solvates, diastereomers, polymorphs, or prodrugs thereof (or pharmaceutical compositions thereof) can be administered by any means known in the art. For example, the compounds or compositions of the present invention can be administered orally, nasally, transdermally, topically, pulmonary, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. Administration can be systemic (e.g., intravenous) or topical. In certain aspects, the route of administration can be intravenous, intramuscularly, subcutaneously, intradermally, intraperitoneally, intrathecally, intrapleurally, intrauterinely, rectally, vaginally, topically, and the like. In certain aspects, the compound is administered subcutaneously.

[0488] The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; an antibacterial agent, such as benzyl alcohol or methyl paraben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate, and an agent for adjusting tonicity, such as sodium chloride or glucose. The pH can be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be packaged in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0489] The compounds or pharmaceutical compositions of the present disclosure can be administered to a subject using any of the many methods currently used for chemotherapy. For example, to treat cancer, the compounds of the present disclosure can be injected directly into a tumor, injected into the bloodstream or body cavity, injected subcutaneously, or administered orally or through the skin using a patch. The selected dose should be sufficient to provide effective treatment, but not so high as to cause unacceptable side effects. The patient's disease state (e.g., cancer, precancerous conditions, etc.) and health should preferably be closely monitored for a reasonable period of time during and after treatment.

[0490] In one aspect, the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, solvates, diastereomers, polymorphs or prodrugs thereof, are administered in a suitable dosage form or formulation prepared by combining a therapeutically effective amount (e.g., an effective level sufficient to achieve the desired therapeutic effect) of a compound of the present disclosure or pharmaceutically acceptable salts, esters, solvates, diastereomers, polymorphs or prodrugs thereof (as active ingredient) with a standard pharmaceutical carrier or diluent according to conventional procedures (i.e., by producing a pharmaceutical composition of the present disclosure). These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to obtain the desired formulation.

[0491] Parenteral dosage forms can be prepared by any means known in the art. For example, sterile injectable aqueous or oily suspensions can be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents.

[0492] Oral dosage forms, such as capsules, tablets, pills, powders, and granules, can be prepared using any suitable method known in the art. For example, the compounds of the present disclosure can be mixed with an enteric material and compressed into tablets. Alternatively, the formulations of the present disclosure can be incorporated into chewable tablets, crushable tablets, tablets that dissolve rapidly in the oral cavity, or mouthwashes.

[0493] For pulmonary (e.g., intratracheal) administration, the compounds of the present disclosure can be formulated with conventional excipients to prepare inhalable compositions in the form of fine powders or aerosolizable liquids. For ocular administration, the compounds of the present disclosure can be formulated with conventional excipients, for example, in the form of eye drops or ocular implants. Excipients useful in eye drops are particularly viscosity-enhancing or gelling agents to minimize losses due to tearing by improving retention in the eye.

[0494] Liquid dosage forms for oral or other administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active agent(s), the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, compositions for ophthalmic, oral, or other systemic delivery may also include adjuvants, such as wetting agents, as well as emulsifiers and suspending agents.

[0495] Commercially available nebulizers for liquid formulations, including jet nebulizers and ultrasonic nebulizers, can be used for administration. Liquid formulations can be directly nebulized, and lyophilized powders can be nebulized after reconstitution. Alternatively, the compounds of the present disclosure can be aerosolized using a fluorocarbon formulation and a metered-dose inhaler, or inhaled as a lyophilized and ground powder.

[0496] The dosage form for topical or transdermal administration of the pharmaceutical composition of the present invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. As required, the activating agent is mixed with a pharmaceutically acceptable carrier and any required preservatives or buffers under aseptic conditions. For example, the skin administration route is realized with aqueous drops, mists, emulsions or creams.

[0497] Transdermal patches can have the added advantage of providing controlled delivery of active ingredients to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate control can be achieved by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0498] Compositions for rectal or vaginal administration may be suppositories, which can be prepared by mixing the compounds of the present disclosure with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature, thereby melting in the rectal or vaginal cavity and releasing the active agent(s). Alternatively, the desired formulation can be administered by release from the lumen of an endoscope after insertion of the endoscope into the rectum of a subject.

[0499] Those skilled in the art are referred to general reference texts for detailed descriptions of known or equivalent technologies discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology ,John Wiley and Sons, Inc. (2005);Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology , John Wiley & Sons,NY; Enna et al., Current Protocols in Pharmacology , John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, PA, 18th edition (1990). Of course, these texts can also be referenced when implementing or using aspects of the present disclosure.

[0500] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the various examples. The provided examples illustrate different components and methods that can be used to practice the present disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, a skilled artisan can identify and adopt other components and methods that can be used to practice the present disclosure. Example

[0501] Example 1: Effects of Compound 20 (shown as Compound A in the figure) on obese and lean mice

[0502] Female C57Bl / 6 mice were surgically ovariectomized (Jackson Lab) at six weeks of age and fed a high-fat diet (HFD) or a low-fat diet (LFD) after recovery until the average weight of mice on the HFD exceeded 40 g. EO771 cells (50,000; from CH3 Biosystems) were then injected into the fourth mammary gland, and when tumors reached approximately 50 mm 3 Treatment with SDX-7320 was initiated at 4:15 pm (subcutaneous, every 4 days, for a total of four doses). Mice were euthanized, and a terminal blood sample was obtained 15 days after the start of dosing. Plasma leptin and total adiponectin were analyzed by MSD. Adipose tissue was dissected and weighed. Tumors were dissected and weighed, and a portion was placed in 10% buffered formalin for histological analysis, while the other portion was placed in ice-cold tissue culture medium for subsequent processing and leukocyte analysis by flow cytometry.

[0503] EO771 tumors grew at a faster rate in obese mice compared to age-matched lean mice ( Figure 1A Compound A significantly attenuated tumor growth in both lean and obese mice ( Figure 1B 、 1C Compound A significantly reduced body weight in both lean and obese mice ( FIG2 ), which was (in part) due to a significant reduction in adipose tissue mass ( FIG3 ).

[0504] Example 2: Effects of Compound 20 (shown as Compound A in the figure) on tumor and serum biomarkers in lean and obese mice

[0505] Compound A significantly reduced leptin levels in obese mice ( Figure 4A ), while compound A significantly increased adiponectin levels in both lean and obese mice ( Figure 4B Compound A significantly reduced the leptin / adiponectin ratio in both lean and obese mice ( Figure 4C ).

[0506] Compound A significantly reduced the level of the immunosuppressive cytokine IL-10 in obese mice ( Figure 5B Therefore, it is expected that the effect of Compound A to reduce circulating IL-10 levels will alter the tumor microenvironment in a manner that reduces the immunosuppressive state of the TME.

[0507] A subset of tumor samples from each group (n=3 / group, except for samples from obese mice treated with Compound A, which consisted of n=2 due to low cell viability in one of the samples) was processed for analysis of leukocyte content by flow cytometry. In particular, based on the elevated CD11b expression of immature myeloid-derived suppressor cells (MDSCs), the expression of + / GR-1+ The researchers used a 3-D-PCR assay to measure the intratumoral abundance of immature myeloid-derived suppressor cell (MDSC) populations. These cells are known to suppress T cell-mediated immunity and enable tumors to evade immune surveillance. While Compound A did not affect the intratumoral abundance of MDSCs in lean mice, treatment with Compound A reduced the abundance of these cells in obese mice by >90%. Figure 6 ).

[0508] EO771 breast tumors were analyzed by immunohistochemistry (IHC) for the nuclear antigen FoxP3, a marker of Tregs (Hori et al., 2003, Science . 299 (5609): 1057–61). The results of this analysis showed that tumors from vehicle-treated obese mice had a large number of FoxP3-positive cells within the tumor and surrounding capillaries ( Figure 7A In contrast, tumors from mice treated with Compound A showed a reduced number of FoxP3-positive cells (in Figure 7B (Indicated by arrows in the figure). This suggests that the tumor microenvironment (TME) is altered by Compound A, resulting in a less immunosuppressive TME due to a decrease in Treg numbers. Slides were counterstained with hematoxylin to visualize cell nuclei.

[0509] Additional IHC analysis of EO771 tumors from obese mice targeted the enzyme arginase-1 (Arg-1), which metabolizes arginine. Within tumors, elevated Arg-1 activity reduces extracellular arginine levels and deprives cytotoxic T lymphocytes of a crucial energy source, leading to reduced tumor-killing activity (Popovic et al., J. Nutr. 137:1681S–1686S, 2007). IHC results showed that tumors from obese mice had robust Arg-1 staining in certain areas of the tumor (T), tumor stroma (S), and surrounding tumor-associated adipocytes (A; Figure 8A In contrast, Arg-1 staining was reduced in tumors from obese mice treated with Compound A, especially within the tumor (T), while staining sometimes remained evident in the tumor stroma (S) and surrounding adipose tissue (A; Figure 8B ).

[0510] Example 3: Effects of Compound 20 (shown as Compound A in the Figure) on Biomarker Expression in Human Cancer Patients

[0511] As part of an ongoing clinical trial (SDX-0101), the following exploratory biomarkers were measured using standard immunological assays in serum from patients with advanced cancer who were treated with Compound A. Compound A was administered subcutaneously as a sterile solution in 5% mannitol / water every seven days or every fourteen days. Results showed that leptin levels were generally decreased in patients treated with Compound A ( Figure 9A ), this is particularly evident when data are expressed as “% change from baseline” ( Figure 9B Note that the leptin data are stratified relative to baseline leptin (> 10 ng / ml). In contrast, levels of another adipokine (e.g., adipose tissue-derived hormone), adiponectin, were generally elevated following treatment with Compound A ( Figure 10A , B). After starting treatment with compound A, the leptin to adiponectin ratio (LAR) also generally decreased ( Figure 11A Insulin is another biomarker in cancer patients with or without metabolic dysfunction. Insulin was measured in cancer patients who were heavily pretreated with Compound A (administered subcutaneously every seven days or every fourteen days). The results showed that insulin levels in patients treated with Compound A ( Figure 15A ) and the percentage change from baseline (for patients with insulin levels above 20 uU / ml) ( Figure 15B ) generally decreased. Insulin alone, although a potent mitogen and a known tumor cell stimulator, does not necessarily account for the effects of insulin resistance. Insulin resistance is considered a negative prognostic factor in cancer patients (Duggan et al., J Clin Oncol (2010) 29:32-39). Here, we show that patients with baseline insulin levels above 20 uU / ml had significantly lower insulin resistance scores (using the HOMA2 IR method), regardless of their obesity status ( Figure 19 ).

[0512] The angiogenic protein vascular endothelial growth factor C (VEGF-C) was measured in the serum of cancer patients before and after treatment with Compound A. For patients with baseline VEGF-C > 200 pg / ml, VEGF-C levels generally decreased after treatment with Compound A ( Figure 11A , B). In addition, serum levels of another important cancer growth factor, insulin-like growth factor-1 (IGF-1), were also analyzed. For patients with baseline IGF-1>100 ng / ml, IGF-1 levels generally decreased after starting treatment with compound A ( Figure 13A, B). Serum levels of bFGF / FGF2, another pro-angiogenic and growth-promoting hormone, were shown to decrease after initiation of treatment with Compound A, particularly in patients whose baseline levels were >5.0 pg / ml ( Figure 14A , B). Note that for serum samples with bFGF / FGF2 levels below the LLOQ of this assay (LLOQ = 2.6 pg / ml), a value of 2.0 pg / ml was assigned to facilitate Figure 14B Data are presented in ("Changes in bFGF").

[0513] Insulin is a potent tumor mitogen. Elevated insulin levels have been reported to be associated with disease progression and mortality in cancer patients (Tsujimoto et al., Int. J. Cancer, 2017, 141, 102–111). Figure 15 shows a general decrease in insulin levels in cancer patients with baseline levels greater than 20 uU / ml. Cancer patients with various tumors were given a range of doses of Compound A (1.7–65 mg / m2). 2 ) and dosing schedule (weekly or biweekly). Figure 19 Improvements in insulin sensitivity were shown in these patients using the HOMA2-IR method of calculating insulin sensitivity.

[0514] This has recently been highlighted for the emerging class of drugs targeting the phosphoinositide 3-kinase (PI3K) enzyme, particularly its catalytic subunit p110. Mechanism-based side effects observed preclinically and clinically include hyperglycemia and hyperinsulinemia (Busaidy et al., 2012, J. Clin. Oncol. 30:2919-2928; Hopkins et al., 2018, Nature, 560(7719):499-503). In normal mice, Compound A (administered subcutaneously every 4 days over a 10-day period prior to administration of the PI3K inhibitor apellix / BYL-719) attenuated the acute hyperglycemia induced by apellix / BYL-719 (45 mg / kg, po; Figure 16 A). Figure 20 and 21 A time-course improvement in hyperinsulinemia (measured via direct insulin and its surrogate, C-peptide) was demonstrated. While blood glucose levels were generally attenuated regardless of when animals were pretreated with Compound A prior to apellisin / BYL-719, insulin levels showed a surprising time-dependent and significant improvement in hyperinsulinemia, as evidenced by C-peptide levels.

[0515] Annexins are a family of calcium-dependent phospholipid-binding proteins that preferentially bind phosphatidylserine (PS). Under normal physiological conditions, PS is primarily localized to the inner leaflet of the plasma membrane (Figure 1). At the onset of apoptosis, PS loses its asymmetric distribution across the phospholipid bilayer and translocates to the outer leaflet of the cell membrane, marking the cell as a target for phagocytosis. Once on the outer surface of the membrane, PS can be detected in a calcium-dependent manner using fluorescently labeled annexin V.

[0516] In early apoptotic cells, the plasma membrane excludes viability dyes, such as 7-aminoactinomycin D (7-AAD). Cells at this stage stain with Annexin V but not with viability dyes, distinguishing them from those in the early stages of apoptosis. However, in late apoptotic cells, the plasma membrane loses integrity, allowing Annexin V to access PS within the cell interior. Viability dyes can be used to separate these late apoptotic and necrotic cells (Annexin V and viability dye positive) from those in the early stages of apoptosis (Annexin V positive, viability dye negative). In this study, Annexin V expression was assessed using the Annexin V PE Apoptosis Detection Kit (Catalog #640934) provided by BioLegend using a BD FACSCanto II flow cytometer. Figure 17 It was shown that the use of the small molecule fumagillin derivatives of the present invention reduced cell survival via apoptosis in a time-dependent manner.

[0517] The Caspase-Glo® 3 / 7 assay from Promega Corp is a homogeneous luminescent assay that measures the activity of caspase-3 and -7. These members of the cysteine ​​aspartate-specific protease (caspase) family play key effector roles in apoptosis in mammalian cells.

[0518] The assay provides a luminescent caspase-3 / 7 substrate containing the tetrapeptide sequence DEVD in a reagent optimized for caspase activity, luciferase activity, and cell lysis. Addition of a single Caspase-Glo® 3 / 7 reagent in an "add-mix-measure" format results in cell lysis, followed by caspase cleavage of the substrate and generation of a "luminescent" luminescent signal generated by luciferase. Luminescence is directly proportional to the amount of caspase activity present. Figure 18 Shown is a time-dependent induction of apoptosis via caspase 3 / 7 signaling at increasing concentrations of the small molecules of the invention.

[0519] Example 4: Treatment of cancer using a combination of Compound 20 (shown as Compound A in the figure) and a PI3K inhibitor

[0520] The following is an example showing that a MetAP2 inhibitor, specifically compound 20 (herein referred to as compound A), can be used in combination with a PI3K inhibitor, specifically apellisin / BYL-719, to treat cancer. In this example, 8-10 week old female nu / nu mice were used, in which estrogen pellets were implanted in the intrascapular region. First, 2.5×10 6 MCF-7 cells (suspended in Matrigel) were injected into the fourth mammary gland of mice (n = 10 / treatment group). 3 At 4 hr post-inoculation, mice were subdivided into treatment groups of n = 10 mice and administered Compound A at the doses shown in Table 2. 24 hours after receiving Compound A, a subset of treatment groups were administered BYL-719 at the doses shown in Table 2. Compound A was administered subcutaneously (SC) and every four days (Q4D). BYL-719 was administered orally (PO) and once daily (QD). A vehicle control was administered orally (PO) once daily (QD).

[0521] Table 2.

[0522] Treatment group name N (mice / treatment group) Dosage of Compound A Dosing regimen of Compound A Administration route of Compound A Dosage of BYL-719 Dosing regimen of BYL-719 Route of administration of BYL-719 vehicle 10 - - - - - - Compound A (8 mg / kg) 10 8 Q4D SC - - - Compound A (16 mg / kg) 10 16 Q4D SC - - - Compound A (8 mg / kg) + BYL-719 (25 mg / kg) 10 8 Q4D SC 25 QD PO Compound A (8 mg / kg) + BYL-719 (45 mg / kg) 10 8 Q4D SC 45 QD PO BYL-719 (25 mg / kg) 10 - - - 25 QD PO BYL-719 (45 mg / kg) 10 - - - 45 QD PO

[0523] Blood glucose levels were assessed at baseline using a glucometer using blood collected from the tail of mice once a week (4 hours after BYL administration) and when mice were euthanized. After euthanasia of surviving mice, a terminal blood sample (cardiac puncture) was obtained, and plasma was prepared from the remaining blood for biomarker analysis. After euthanasia, tumors were dissected, weighed, and divided into two parts—one half was placed in buffered formalin, and the other half was homogenized in RIPA buffer containing phosphatase and protease inhibitors and subsequently frozen at -70°C.

[0524] Figure 22 Shown are changes in MCF-7 tumor volume (% change from baseline) in mice treated with vehicle control, 8 mg / kg of Compound A, or 16 mg / kg of Compound A. Figure 23 Shown are changes in MCF-7 tumor volume in mice treated with vehicle control, 8 mg / kg of Compound A, 8 mg / kg of Compound A in combination with 25 mg / kg of BYL-719, or 25 mg / kg of BYL-719 alone. Figure 24 Shown are changes in MCF-7 tumor volume in mice treated with vehicle control, 8 mg / kg of Compound A, 8 mg / kg of Compound A in combination with 45 mg / kg of BYL-719, or 45 mg / kg of BYL-719 alone. Figure 22、 23 Comparison of 24 and 25 showed that the effect of treatment with Compound A alone was less than that observed when Compound A was used in combination with BYL-719. The combination of Compound A and BYL-719 showed a synergistic effect (with 25 mg / kg BYL-719) or an additive effect (with 45 mg / kg BYL-719).

[0525] Figure 25 Shown are the changes in tumor volume at day 37 in all treatment groups. Figure 25 The results show that the combination of Compound A and BYL-719 at a low BYL-719 dose (25 mg / kg) or a high BYL-719 dose (45 mg / kg) significantly attenuated tumor growth when compared to the single-agent activity of Compound A or BLY-719 alone. Therefore, the results of this example suggest that MetAP2 inhibitors can be used in combination with PI3K inhibitors to treat cancer.

[0526] Example 5: Treatment of cancer using a combination of Compound 20 (shown as Compound A in the figure) and an AKT inhibitor

[0527] The following example demonstrates that MetAP2 inhibitors, specifically Compound 20 (herein referred to as Compound A), can be used in combination with AKT inhibitors, specifically AZD5363 / capavasertib, to treat cancer. In this example, 8-10 week-old male C57BI / 6 mice were used. First, mice (n = 8 per treatment group) were administered vehicle control (5% mannitol), Compound A alone, Compound A in combination with AZD5363, or AZD5363 alone at the doses shown in Table 3. Compound A was administered subcutaneously (SC) and every four days (Q4D) at a dose of 8 mg / kg. AZD5363 was administered orally (PO) and once daily (QD) at a dose of 200 mg / kg. The vehicle control was administered orally (PO) once daily (QD). Blood glucose was monitored using 10 μl of blood drawn from the mouse tail using a glucometer, starting before AZD5363 administration (time 0) and then again at different time points (15, 30, 60, 90, 120, and 180 minutes) after AZD5363 administration. Figure 26 As shown in , a single dose of AZD5363 (200 mg / kg, oral) administered to normal adult male C57Bl / 6 mice significantly and rapidly increased blood glucose compared with vehicle, whereas pre-treatment of mice with SDX-7320 (8 mg / kg, subcutaneous, Q4D, for a total of 4 doses) significantly attenuated the AZD5363-induced blood glucose elevation.

[0528] Table 3

[0529] N (mice / group) Dosage (mg / kg) way Time before drug administration (h, d) Number of doses vehicle 8 - PO Compound A 8 8 (Q4D) SC -14 d 3 Compound A + AZD5363 8 8(Q4D) / 200(QD) SC / PO -14 d 3 / 1 AZD5363 8 200 (QD) PO 0 1 Total = 32

[0530] Without wishing to be bound by theory, inhibitors of the PI3K / Akt / mTOR pathway can disrupt insulin signaling, and this may provide therapeutic benefit by inhibiting the growth of certain tumors, particularly those harboring activating mutations in this pathway. However, due to the simultaneous impact on the normal physiological control of systemic blood glucose homeostasis, such inhibitors may also cause hyperglycemia and subsequent hyperinsulinemia. Hyperglycemia / hyperinsulinemia has been observed as a side effect in preclinical models and in patients participating in clinical trials of novel PI3K / Akt / mTOR inhibitors. Alleviating induced hyperglycemia / hyperinsulinemia may provide a greater benefit in reducing tumor growth and increasing survival than PI3K inhibitors alone. Thus, this example demonstrates that the conjugates and compounds of the present disclosure, including Compound A, mitigate hyperglycemia induced by Akt inhibitors such as AZD5363. Compound A's mitigation of these side effects may provide benefits in terms of enhanced anti-tumor activity when administered in combination with AZD5363, making the combination of the conjugates / compounds of the present disclosure with Akt inhibitors a powerful approach for treating cancer in subjects.

[0531] Example 6 Treatment of cancer using a combination of a MetAP2 inhibitor and a PI3K inhibitor

[0532] The following is an example demonstrating that MetAP2 inhibitors, specifically ZGN-1061, can be used in combination with PI3K inhibitors, specifically BYL-719, to treat cancer and alleviate treatment-induced metabolic dysfunction. In this example, 10-12 week old male C57BI / 6 mice were used. Mice (n = 8 per treatment group) were administered vehicle control (10 mM phosphate in 5% mannitol, pH 7.2), ZGN-1061 alone, ZGN-1061 in combination with BYL-719, or BYL-719 alone at the doses shown in Table 4. The route of administration and dosing schedule for each compound / compound combination are shown in Table 4. In Table 4, the time of administration is indicated relative to the time of BYL-719 administration. Blood glucose was monitored using 10 μl of blood drawn from the mouse tail and a glucometer, starting before BYL-719 administration (time 0) and then again at different time points after BYL-719 administration (15, 30, 60, 90, 120, and 180 minutes).

[0533] Table 4

[0534] N (mice / group) Dosage (mg / kg) way Dosing time (hours, relative to BYL-719) Number of doses vehicle 8 - PO 0 ZGN-1061 8 0.5 SC -24 h 1 ZGN-1061 8 0.5 (QD) SC -72 h 3 (QD) ZGN-1061+ BYL-719 8 0.5 / 45 SC / PO -4 h / 0 1 / 1 ZGN-1061+ BYL-719 8 0.5 / 45 SC / PO -24 h / 0 1 / 1 ZGN-1061+ BYL-719 8 0.5 / 45 SC / PO -72 h / 0 3 (QD) / 1 BYL-719 8 45 PO 0 1 Total = 56

[0535] like Figure 27As shown in , administration of BYL-719 induced robust hyperglycemia. Figure 28 As shown in , pretreatment of mice with a MetAP2 inhibitor (ZNG-1061) at various times before BYL-719 administration attenuated BYL-719-induced hyperglycemia. These results suggest that MetAP2 inhibitors, such as ZNG-1061, can attenuate PI3K inhibitor-induced hyperglycemia and suggest that the combination of MetAP2 inhibitors and PI3K inhibitors could be useful in treating cancer patients, particularly those with treatment-induced hyperglycemia.

Claims

1. Use of at least one therapeutically effective amount of at least one compound of the formula: or a pharmaceutically acceptable salt thereof and at least one therapeutically effective amount of at least one second active agent in the preparation of a medicament for treating cancer in a subject in need thereof: in, x is 1 to 450; y is 1 to 30; n is 1 to 100; wherein the at least one second active agent comprises alpelisib (BYL-719) or capivasertib (AZD5363), wherein administration of the at least one compound reduces hyperglycemia caused by the at least one second active agent.

2. The method of claim 1, wherein the at least one second active agent comprises alpelisib (BYL-719).

3. The use according to claim 1, wherein the at least one second active agent comprises capivasertib (AZD5363).

4. The use according to claim 1, wherein the metabolic dysfunction is induced by the at least one second active agent.

5. The use according to claim 4, wherein the metabolic dysfunction is at least one of hyperglycemia, hyperinsulinemia, excess visceral fat, elevated leptin levels, decreased adiponectin levels, a high leptin / adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, or any combination thereof.

6. The use according to claim 1, wherein the ratio of x to y is 30:1 to 3:

1.

7. The method according to claim 1, wherein the ratio of x to y is 11:

1.

8. The use according to claim 1, wherein the therapeutically effective amount of the at least one compound is 0.0001 mg / kg to 5 mg / kg body weight per day.

9. The use according to claim 1, wherein the therapeutically effective amount of the at least one compound is 0.001 to 0.1 mg / kg body weight per day.

10. The use according to claim 1, wherein the at least one compound is used for: (a) Administer once a week; (b) administered on a q4d dosing schedule; (c) administered on a q7d dosing schedule; (d) administered once every two weeks; or (e) Apply 1 to 4 times per month.

11. The use of claim 1, wherein the subject is treated for at least six months.

12. The use according to claim 1, wherein the subject is treated for at least one year.

13. The use according to claim 1, wherein the subject is treated for at least two years.

14. The use according to claim 1, wherein the subject is treated for at least three years.

15. The use according to claim 1, wherein the at least one compound is for parenteral administration.

16. The use according to claim 1, wherein the at least one compound is for subcutaneous administration.

17. The use according to claim 1, wherein the cancer is breast cancer, prostate cancer, esophageal cancer, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gallbladder cancer, liver cancer, clear cell renal carcinoma, melanoma, multiple myeloma or a combination thereof.

18. The use according to claim 1, wherein the cancer is castration-resistant prostate cancer.

19. The use according to claim 17, wherein the cancer is breast cancer.

20. The use according to claim 19, wherein the breast cancer is triple-negative breast cancer.

21. The use according to claim 19, wherein the breast cancer is Her2+ breast cancer.

22. The use according to claim 19, wherein the breast cancer is HR+ breast cancer.

23. The use according to claim 22, wherein the HR+ breast cancer is HR+ / Her2- breast cancer.

24. The use according to claim 23, wherein the HR+ / Her2- breast cancer is postmenopausal HR+ / Her2- breast cancer.

25. The use according to claim 1, wherein the at least one compound and the at least one second active agent are for administration sequentially or in a substantially simultaneous manner.

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