Combination therapy with peptide epoxyketones

Abstract

The invention provides combination therapy, wherein one or more other therapeutic agents are administered agents are administered with peptide epoxyketones or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to treating cancer with a peptide epoxyketone administered in combination with another therapeutic agent.

1 . A method for treating cancer, comprising administering a peptide epoxyketone proteasome inhibitor or a pharmaceutically acceptable salt thereof; and one or more other therapeutic agents, wherein the combination shows efficacy that is greater than the efficacy of either agent being administered alone. 
     
     
         2 . A method of  claim 1 , wherein the peptide epoxyketone has a structure of Formula (2), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein each A is independently selected from C═O, C═S, and SO 2 ; or
 A is optionally a covalent bond when adjacent to an occurrence of Z; 
 L is absent or is selected from C═O, C═S, and SO 2 ; 
 M is absent or is C 1-12 alkyl; 
 Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
 X is O; 
 Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ; 
 each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
 Z is optionally a covalent bond when adjacent to an occurrence of A; 
 R 1 , R 2 , R 3 , and R 4  are each independently selected from optionally substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
 R 5  is N(R 6 )LQR 7 ; 
 R 6 , R 12 , R 13 , and R 14  are independently selected from hydrogen, OH, and C 1-6 alkyl; 
 R 7  is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, R 8 ZAZ—C 1-6 alkyl-, R 11 Z—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, R 8 ZAZ—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-12 alkyl-, (R 10 ) 3 N—C 1-12 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or 
 R 6  and R 7  together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ, or C 1-6 alkyl-A, thereby forming a ring; 
 R 8  and R 9  are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl; 
 each R 10  is independently selected from hydrogen and C 1-6 alkyl; 
 R 11  is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, 
 R 15  and R 16  are independently selected from hydrogen and C 1-6 alkyl, or R 15  and R 16  together form a 3- to 6-membered carbocyclic or heterocyclic ring; and 
 R 17  and R 18  are independently selected from hydrogen, a metal cation, C 1-6 alkyl, and C 1-6 aralkyl, or R 17  and R 18  together represent C 1-6 alkyl, thereby forming a ring; 
 provided that when R 6 , R 12 , R 13 , and R 14  are H or CH 3 , and Q is absent, LR 7  is not hydrogen, unsubstituted C 1-6 alkylC═O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl(trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and 
 in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
 
     
     
         3 . A method of  claim 1 , wherein the peptide epoxyketone has a structure of Formula (4), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein each A is independently selected from C═O, C═S, and SO 2 ; or
 A is optionally a covalent bond when adjacent to an occurrence of Z; 
 L is absent or is selected from C═O, C═S, and SO 2 ; 
 M is absent or is C 1-12 alkyl; 
 Q is absent or is selected from O, NH, and N—C 1-6 alkyl; 
 X is O; 
 Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ; 
 each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or 
 Z is optionally a covalent bond when adjacent to an occurrence of A; 
 R 2  and R 4  are each independently selected from optionally substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl; 
 R 5  is N(R 6 )LQR 7 ; 
 R 6  is selected from hydrogen, OH, and C 1-6 alkyl, preferably C 1-6 alkyl; 
 R 7  is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, R 8 ZAZ—C 1-8 alkyl-, R 11 Z—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, R 8 ZAZ—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-12 alkyl-, (R 10 ) 3 N—C 1-12 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or 
 R 6  and R 7  together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ, or C 1-6 alkyl-A, thereby forming a ring; 
 R 8  and R 9  are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl; 
 each R 10  is independently selected from hydrogen and C 1-6 alkyl; and 
 R 11  is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, 
 provided that when R 6  is H or CH 3  and Q is absent, LR 7  is not hydrogen, unsubstituted C 1-6 alkylC═O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl(trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and 
 in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond. 
 
     
     
         4 . A method of  claim 1 , wherein the peptide epoxyketone has a structure of Formula (10), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 L is absent or is selected from —CO 2  or —C(═S)O; 
 X is O; 
 Y is NH, N-alkyl, O, or C(R 9 ) 2 ; 
 Z is O or C(R 9 ) 2 ; 
 R 1 , R 2 , R 3 , and R 4  are all hydrogen; 
 each R 5 , R 6 , R 7 , R 8 , and R 9  is independently selected from hydrogen and optionally substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, wherein substituents may include, but are not limited to, alkyl, amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; 
 R 10  and R 11  are independently selected from hydrogen and C 1-6 alkyl, or R 10  and R 11  together form a 3- to 6-membered carbocyclic or heterocyclic ring; 
 R 12  and R 13  are independently selected from hydrogen, a metal cation, C 1-6 alkyl, and C 1-6 aralkyl, or R 12  and R 13  together represent C 1-6 alkyl, thereby forming a ring; 
 m is an integer from 0 to 2; and 
 n is an integer from 0 to 2. 
 
     
     
         5 . A method of  claim 1 , wherein the peptide epoxyketone has a structure of Formula (12), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       where X is O;
 R 1 , R 2 , R 3 , and R 4  are all hydrogen; and 
 R 5 , R 6 , R 7 , and R 8  are independently selected from hydrogen and optionally substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, wherein substituents may include, but are not limited to, amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether. 
 
     
     
         6 . A method of  claim 1 , wherein the peptide epoxyketone has the following structure, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A method of  claim 1 , wherein the effects of the peptide epoxyketone and the one or more other therapeutic agents are synergistic. 
     
     
         8 . A method of  claim 1 , wherein the effects of the peptide epoxyketone and the one or more other therapeutic agents are additive. 
     
     
         9 . A method of  claim 1 , wherein the peptide epoxyketone and the one or more other therapeutic agents are administered simultaneously. 
     
     
         10 . A method of  claim 1 , wherein the one or more other therapeutic agents are administered within about 5 minutes to within about 48 hours prior to or after administration of the peptide epoxyketone. 
     
     
         11 . A method of  claim 10 , wherein the one or more other therapeutic agents are administered within about 5 minutes to within about 1 hour prior to or after administration of the peptide epoxyketone. 
     
     
         12 . A method of  claim 1 , wherein the cancer is selected from hematological malignancies, solid tumors, neuroblastoma, or melanoma. 
     
     
         13 . A method of  claim 12 , wherein the cancer is selected from mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias (e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), and adult T-cell leukemia/lymphoma (ATLL)), acute lymphocytic leukemia, acute myelogenous leukemia (e.g., acute monocytic leukemia and acute promyelocytic leukemia), chronic lymphocytic leukemia (e.g., chronic B cell leukemia), chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma (e.g., Burkitt's lymphoma), myeloma, multiple myeloma, and myelodysplastic syndrome. 
     
     
         14 . A method of  claim 12 , wherein the cancer is selected from multiple myeloma and lymphoma. 
     
     
         15 . A method of  claim 12 , wherein the cancer is selected from mesothelioma, brain neuroblastoma, retinoblastoma, glioma, Wilms' tumor, bone cancer and soft-tissue sarcomas, head and neck cancers (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal, and colon), lung cancer (e.g., small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and adenocarcinoma), breast cancer, pancreatic cancer, basal cell carcinoma, metastatic skin carcinoma, squamous cell carcinoma (both ulcerating and papillary type), stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary carcinoma, osteosarcoma, soft-tissue sarcoma, Ewing's sarcoma, reticulum cell sarcoma, and Kaposi's sarcoma. 
     
     
         16 . A method of  claim 15 , wherein the cancer is selected from ovarian cancer, non-small cell lung cancer, and colorectal cancer. 
     
     
         17 . A method of  claim 1 , wherein the other therapeutic agent is an HDAC inhibitor. 
     
     
         18 . A method of  claim 17 , wherein the HDAC inhibitor is selected from trichostatin A, depsipeptide, apicidin, A-161906, scriptaid, PXD-101, CHAP, butyric acid, depudecin, oxamflatin, phenylbutyrate, valproic acid, SAHA (Vorinostat), MS275 (N-(2-Aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide), LAQ824/LBH589, C1994, and MGCD0103. 
     
     
         19 . A method of  claim 18 , wherein the HDAC inhibitor is SAHA. 
     
     
         20 . A method of  claim 1 , wherein the other therapeutic agent is an antibiotic. 
     
     
         21 . A method of  claim 20 , wherein the antibiotic is selected from dactinomycin (actinomycin D), daunorubicin, doxorubicin and idarubicin. 
     
     
         22 . A method of  claim 21 , wherein the antibiotic comprises doxorubicin. 
     
     
         23 . A method of  claim 1 , wherein the other therapeutic agent is a taxane. 
     
     
         24 . A method of  claim 23 , wherein the taxane is selected from paclitaxel and docetaxel. 
     
     
         25 . A method of  claim 1 , wherein the other therapeutic agent is an antiproliferative/antimitotic alkylating agents. 
     
     
         26 . A method of  claim 25 , wherein the antiproliferative/antimitotic alkylating agent is a nitrogen mustard. 
     
     
         27 . A method of  claim 26 , wherein the nitrogen mustard is selected from mechlorethamine, ifosphamide, cyclophosphamide and analogs, melphalan, and chlorambucil. 
     
     
         28 . A method of  claim 1 , wherein the other therapeutic agent is a platinum coordination complex. 
     
     
         29 . A method of  claim 28 , wherein the platinum coordination complex is selected from cisplatin and carboplatin. 
     
     
         30 . A method of  claim 1 , wherein the other therapeutic agent is a steroid. 
     
     
         31 . A method of  claim 30 , wherein the steroid is selected from hydrocortisone, dexamethasone, methylprednisolone and prednisolone. 
     
     
         32 . A method of  claim 31 , wherein the steroid is dexamethasone. 
     
     
         33 . A method of  claim 1 , wherein the other therapeutic agent is an immunomodulator. 
     
     
         34 . A method of  claim 33 , wherein the immunomodulator is selected from thalidomide, CC-4047 (Actimid), and lenalidomide (Revlimid). 
     
     
         35 . A method of  claim 34 , wherein the immunomodulator is lenalidomide. 
     
     
         36 . A method of  claim 1 , wherein the other therapeutic agent is a topoisomerase inhibitor. 
     
     
         37 . A method of  claim 36 , wherein the topoisomerase inhibitor is selected from irinotecan, topotecan, camptothecin, lamellarin D, and etoposide. 
     
     
         38 . A method of  claim 1 , wherein the other therapeutic agent is an m-TOR inhibitor. 
     
     
         39 . A method of  claim 38 , wherein the m-TOR inhibitor is selected from CCI-779, AP23573 and RAD-001. 
     
     
         40 . A method of  claim 1 , wherein the other therapeutic agent is a protein kinase inhibitor. 
     
     
         41 . A method of  claim 40 , wherein the protein kinase inhibitor is selected from sorafenib, imatinib, dasatinib, sunitinib, pazopanib, and nilotinib. 
     
     
         42 . A method of  claim 41 , wherein the protein kinase inhibitor is sorafenib. 
     
     
         43 . A method for treating autoimmune diseases, comprising administering a peptide epoxyketone or a pharmaceutically acceptable salt thereof; and one or more other therapeutic agents, wherein the combination shows efficacy that is greater than the efficacy of either agent being administered alone.