Treatment for tumors driven by metabolic dysfuction

Abstract

The present disclosure relates to modified or polymer conjugated MetAP2 inhibitors. The present disclosure also relates to methods of treating metabolically-driven diseases and disorders, such as certain cancers.

1 .- 51 . (canceled) 
     
     
         52 . A method of treating cancer in a subject in need thereof comprising administering to the subject at least one therapeutically effective amount of at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, wherein the at least one polymer conjugate comprises the Formula 
       
         
           
           
               
               
           
         
       
       wherein, independently for each occurrence,
 R 4  is H or C 1 -C 6  alkyl; 
 R 5  is H or C 1 -C 6  alkyl; 
 R 6  is C 2 -C 6  hydroxyalkyl; 
 Z is —NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-L or —NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W; 
 AA 1  is glycine, alanine, or H 2 N(CH 2 ) m CO 2 H, wherein m is 2, 3, 4 or 5; 
 AA 2  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; 
 AA 3  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; 
 AA 4  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; 
 AA 5  is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; 
 AA 6  is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H 2 N(CH 2 ) m CO 2 H, wherein m is 2, 3, 4 or 5; 
 L is —OH, —O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, —NH 2 , —NH(C 2 -C 6  hydroxyalkyl), halide or perfluoroalkyloxy; 
 Q is NR, O, or S; 
 X is M-(C(R) 2 ) p -M-J-M-(C(R) 2 ) p -M-V; 
 M is a bond, or C(O); 
 J is a bond, or ((CH 2 ) q Q) r , C 5 -C 8  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  taken together with Y forms a heterocyclic ring; 
         R 10  is amido or a bond; 
         R 11  is H or alkyl; 
         W is a Methionine aminopeptidase 2 (MetAP2) inhibitor moiety or alkyl; 
         x is in the range of 1 to about 450; 
         y is in the range of 1 to about 30; 
         n is in the range of 1 to about 100; 
         p is 0 to 20; 
         q is 2 or 3; 
         r is 1, 2, 3, 4, 5, or 6; and 
         at least one therapeutically effective amount of at least one second active agent. 
       
     
     
         53 . The method of  claim 52 , wherein the second active agent comprises at least one kinase inhibitor. 
     
     
         54 . The method of  claim 53 , wherein the at least one kinase inhibitor is a multi-kinase inhibitor; a serine/threonine kinase inhibitor, a tyrosine kinase inhibitor, an MTOR inhibitor, a PI3K inhibitor, an AKT inhibitor or any combination thereof. 
     
     
         55 . The method of  claim 52 , wherein the second active agent comprises Fulvestrant 
     
     
         56 . The method of  claim 52 , wherein the second active agent comprises a chemotherapeutic agent. 
     
     
         57 . The method of  claim 52 , wherein the chemotherapeutic agent comprises an alkylating agent, an antibiotic, an anti-metabolite, a detoxifying agent, an interferon, a polyclonal or monoclonal antibody, an EGFR inhibitor, an FGFR inhibitor, a HER2 inhibitor, a PI3K inhibitor, an AKT inhibitor, a histone deacetylase inhibitor, a hormone, a mitotic inhibitor, an MTOR inhibitor, a multi-kinase inhibitor, a serine/threonine kinase inhibitor, a tyrosine kinase inhibitor, a VEGF/VEGFR inhibitor, a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, a cytidine analogue drug, an anti-neoplastic agent, an anti-proliferative agent, eribulin or eribulin derivative or any combination thereof. 
     
     
         58 . The method of  claim 52 , wherein the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, and the second active agent are administered sequentially or in a substantially simultaneous manner. 
     
     
         59 . The method of  claim 52 , wherein the second active agent is administered at a time point after the administration of the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof. 
     
     
         60 . The method of  claim 52 , wherein the subject has a metabolic dysfunction, wherein the metabolic dysfunction is elevated fasting insulin levels, excessive visceral adiposity, elevated leptin levels, low adiponectin levels, a high leptin-to-adiponectin ratio, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance or any combination thereof. 
     
     
         61 . The method of  claim 60 , wherein the metabolic dysfunction is elevated fasting insulin levels. 
     
     
         62 . The method of  claim 52 , wherein the cancer is selected from a group consisting of HR+/Her2− breast cancer, breast cancer, prostate cancer, esophageal carcinoma, colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gall bladder cancer, liver cancer, clear-cell renal cancer, melanoma, multiple myeloma, thyroid cancer or combinations thereof. 
     
     
         63 . The method of  claim 52 , wherein Z is represented by a formula selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         64 . The method of  claim 52 , wherein the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, comprises the Formula 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         65 . The method of  claim 52 , wherein the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, comprises the Formula 
       
         
           
           
               
               
           
         
       
     
     
         66 . The method of  claim 52 , wherein R 4  is methyl. 
     
     
         67 . The method of  claim 52 , wherein R 5  is methyl. 
     
     
         68 . The method of  claim 52 , wherein R 6  is 2-hydroxypropyl. 
     
     
         69 . The method of  claim 52 , wherein Z is —NH— AA 6 -C(O)-Q-X—Y—C(O)—W. 
     
     
         70 . The method of  claim 69 , wherein AA 6  is glycine. 
     
     
         71 . The method of  claim 52 , wherein Z is —NH— AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W. 
     
     
         72 . The method of  claim 71 , wherein
 (i) AA 5  is leucine and AA 6  is glycine;   (ii) AA 5  is valine and AA 6  is glycine;   (iii) AA 5  is phenylalanine and AA 6  is glycine; or   (iv) AA 5  is glycine and AA 6  is glycine.   
     
     
         73 . The method of  claim 52 , wherein Z is —NH— AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W. 
     
     
         74 . The method of  claim 73 , wherein
 (i) AA 5  is leucine and each of AA 3 , AA 4 , or AA 6  is glycine;   (ii) AA 5  is valine and each of AA 3 , AA 4 , or AA 6  is glycine;   (iii) AA 5  is phenylalanine and each of AA 3 , AA 4 , or AA 6  is glycine;   (iv) AA 3  is glycine, AA 4  is phenylalanine, AA 5  is leucine and AA 6  is glycine; or   (v) AA 3 , AA 4 , AA 5  and AA 6  is glycine.   
     
     
         75 . The method of  claim 52 , wherein -Q-X—Y is 
       
         
           
           
               
               
           
         
       
     
     
         76 . The method of  claim 52 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         77 . The method of  claim 52 , wherein the ratio of x toy is in the range of about 30:1 to about 3:1. 
     
     
         78 . The method of  claim 52 , wherein the ratio of x to y is about 11:1. 
     
     
         79 . The method of  claim 52 , wherein the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, is administered about once per week, 1 to 5 times per week, every three to four days once every two weeks, or about 1 to 4 times per month 
     
     
         80 . The method of  claim 52 , wherein the at least one therapeutically effective amount of the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, is about 1 mg/m 2  to about 50 mg/m 2 , about 5 mg/m 2  to about 25 mg/m 2 , about 5 mg/m 2  to about 50 mg/m 2 , about 5 mg/m 2  to about 15 mg/m 2 , or about 5 mg/m 2  to about 10 mg/m 2 . 
     
     
         81 . The method of  claim 52 , wherein the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, is provided as a pharmaceutical composition comprising the at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, and a pharmaceutically acceptable carrier.