Peptide epoxyketone proteasome inhibitors in combination with pim kinase inhibitors for treatment of cancers

Abstract

This disclosure provides methods of treating a cancer in a patient using a peptide epoxyketone proteasome inhibitor in combination with a PIM kinase inhibitor.

What is claimed: 
     
         1 . A method for the treatment of a cancer in a patient, the method comprising administering to the patient
 (a) a therapeutically effective amount of a proteasome inhibitor having a structure of:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and
 (b) a PIM kinase inhibitor, or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method of  claim 1 , wherein the proteasome inhibitor has a structure of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the proteasome inhibitor has a structure of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of any one of  claims 1  to  3 , wherein the PIM kinase inhibitor is orally bioavailable. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the PIM kinase inhibitor is selective for one or more kinases selected from the group consisting of PIM-1, PIM-2, and PIM-3. 
     
     
         6 . The method of  claim 5 , wherein the PIM kinase inhibitor is selective for PIM-2. 
     
     
         7 . The method of any one of  claims 1  to  4 , wherein the PIM kinase inhibitor is selected from the group consisting of: 7-chloro-9-ethyl-6-hydroxyisoxazolo[3,4-b]quinoline-3,4(1H,9H)-dione; 2-[[3-(3-chloro-4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]amino]butan-1-ol; (Z)-5-(4-propoxybenzylidene)thiazolidine-2,4-dione; (Z)-5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione; N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine; N′-(1-(4-Chloro-2-hydroxyphenyl)propylidene)-2-((3-morpholinopropyl)amino)isonicotinohydrazide; 5-amino-2-(2,6-difluorophenyl)-N-(5-(4-(methylamino)butoxy)isothiazol-4-yl)thiazole-4-carboxamide; 2-(2,6-difluorophenyl)-N-(5-(4-hydroxy-4-methylpentyloxy)isothiazol-4-yl)-5-(methylamino)thiazole-4-carboxamide; (Z)-5-((2-(4-(((6-(furan-2-yl)pyridin-2-yl)methylamino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione; (S)-5-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide; and N-(4-((3S,5R)-3-amino-5-methylpiperidin-1-yl)pyridin-3-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of any one of  claims 1  to  7 , wherein the cancer is one selected from the group consisting of: bone cancer, gynecological cancer, breast cancer, hematological malignancy, skin cancer, liver cancer, kidney cancer, pancreatic cancer, brain cancer, lung cancer, and prostate cancer. 
     
     
         9 . The method of any one of  claims 1  to  7 , wherein the cancer is a hematological malignancy. 
     
     
         10 . The method of  claim 9 , wherein the hematological malignancy is selected from the group consisting of: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, AIDS-related lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, mycosis fungoides, primary central nervous system lymphoma, Sézary syndrome, Waldenström macroglobulinemia, chronic myeloproliferative disorders, Langerhans cell histiocytosis, multiple myeloma, plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, and myeloproliferative neoplasms. 
     
     
         11 . The method of  claim 9 , wherein the hematological malignancy is selected from the group consisting of: AIDS-related lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, mycosis fungoides, primary central nervous system lymphoma, Sézary syndrome, Waldenström macroglobulinemia, chronic myeloproliferative disorders, Langerhans cell histiocytosis, multiple myeloma, and plasma cell neoplasms. 
     
     
         12 . The method of  claim 9 , wherein the hematological malignancy is selected from the group consisting of: B-cell lymphoma and multiple myeloma. 
     
     
         13 . The method of  claim 12 , wherein the hematological malignancy is multiple myeloma. 
     
     
         14 . The method of any one of  claims 1  to  13 , wherein the patient is one in whom PIM-2 kinase is overexpressed. 
     
     
         15 . The method of any one of  claims 1  to  14 , wherein the proteasome inhibitor and the PIM kinase inhibitor are administered concurrently. 
     
     
         16 . The method of any one of  claims 1  to  14 , wherein the proteasome inhibitor and the PIM kinase inhibitor are administered sequentially. 
     
     
         17 . The method of  claim 16 , wherein the proteasome inhibitor is administered prior to the PIM kinase inhibitor. 
     
     
         18 . The method of  claim 16 , wherein the proteasome inhibitor is administered after the PIM kinase inhibitor. 
     
     
         19 . A proteasome inhibitor for use in treating cancer in a patient, wherein the proteasome inhibitor has a structure of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 and is for administration with a PIM kinase inhibitor, or pharmaceutically acceptable salt thereof. 
 
     
     
         20 . Use of a proteasome inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer in a patient, wherein the proteasome inhibitor has a structure of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and
 the proteasome inhibitor is for administration with a PIM kinase inhibitor, or a pharmaceutically acceptable salt thereof.