Uses of Bcl-2 Antagonists for Treating Cancer and Diagnostics Related Thereto

Abstract

In certain embodiments, this disclosure relates to method of treating and diagnosing cancer by administering a Bcl-2 inhibitor optionally in combination with a mitochondrial complex II inhibitor. In certain embodiments, a subject is diagnosed with, exhibiting symptoms of, or at risk of cancer wherein the cancer is a hematological malignancy such as multiple myeloma, leukemia, or lymphoma.

1 . A method of treating cancer comprising administering an effective amount of a Bcl-2 inhibitor in combination with a mitochondrial complex II inhibitor to a subject in need thereof. 
     
     
         2 . The method of  claim 1 , wherein the mitochondrial complex II inhibitor is thenoyltrifluoroacetone or atpenin A5. 
     
     
         3 . The method of  claim 1 , wherein the Bcl-2 inhibitor is venetoclax or navitoclax. 
     
     
         4 . The method of  claim 1  wherein the Bcl-2 inhibitor has the following formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, wherein 
         A 1  is C(A 2 ); 
         A 2  is H, F, Br, I, or Cl; 
         B 1  is R 1 , NHR 1 , NHC(O)R 1 , F, Br, I, or Cl; 
         D 1  is H, F, Br, I, or Cl; 
         E 1  is H; and 
         Y 1  is H, CN, NO 2 , F, Cl, Br, I, CF 3 , R 17 , OR 17 , SR 17 , SO 2 R 17 , or C(O)NH 2 ; 
         R 1  is R 4  or R 5 ; 
         R 4  is cycloalkyl or heterocycloalkyl; 
         R 5  is alkyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of R 7 , OR 7 , NHR 7 , N(R 7 ) 2 , CN, OH, F, Cl, Br, and I; 
         R 7  is R 8 , R 9 , R 10 , or R 11 ; 
         R 8  is phenyl; 
         R 9  is heteroaryl; 
         R 10  is cycloalkyl, cycloalkenyl, or heterocycloalkyl; each of which is unfused or fused with R 10A ; R 10A  is heteroarene; 
         R 11  is alkyl, which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of R 12 , OR 12 , and CF 3 ; 
         R 12  is R 14  or R 16 ; 
         R 14  is heteroaryl; 
         R 16  is alkyl; 
         R 17  is alkyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of R 22 , F, Cl, Br and I; 
         R 22  is heterocycloalkyl; 
         wherein the cyclic moieties represented by R 4 , R 8 , R 10 , R 22 , are independently unsubstituted or substituted with one or two or three or four or five substituents independently selected from the group consisting of R 57A , R 27 , OR 57 , SO 2 R 57 , C(O)R 57 , C(O)OR 57 , C(O)N(R 57 ) 2 , NH 2 , NHR 57 , N(R 57 ) 2 , NHC(O)R 57 , NHS(O) 2 R 57 , OH, CN, (O), F, Cl, Br and I; 
         R 57A  is spiroalkyl or spiroheteroalkyl; 
         R 57  is R 58 , R 60 , or R 61 ; 
         R 58  is phenyl; 
         R 60  is cycloalkyl or heterocycloalkyl; 
         R 61  is alkyl, which is unsubstituted or substituted with one or two or three substituents independently selected from the group consisting of R 62 , OR 62 , N(R 62 ) 2 , C(O)OH, CN, F, Cl, Br, and I; 
         R 62  is R 65  or R 66 ; 
         R 65  is cycloalkyl or heterocycloalkyl; 
         R 66  is alkyl, which is unsubstituted or substituted with OR 67 ; 
         R 67  is alkyl; 
         wherein the cyclic moieties represented by R 57A , R 58 , and R 60  are unsubstituted or substituted with one or two or three or four substituents independently selected from the group consisting of R 68 , F, Cl, Br, and I; 
         R 68  is R 71  or R 72 ; 
         R 71  is heterocycloalkyl; and 
         R 72  is alkyl, which is unsubstituted or substituted with one or two F. 
       
     
     
         5 . The method of  claim 1 , the Bcl-2 inhibitor has the following formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof wherein, 
         A 1  is N or CH; 
         B 1  is OR 1  or NHR 1 ; 
         Y 1  is CN, NO 2 , CF 3 , F or Cl; 
         R 1  is (CH 2 ) n R 2 ; 
         R 2  is cycloalkyl or heterocyclyl; wherein the heterocyclyl and cycloalkyl are optionally substituted with one or more independently selected R 4 , OR 4 , OH, CN, or F; 
         R 3  is heteroaryl; wherein the heteroaryl is optionally substituted with one or more independently selected NH 2 , C 1 , or F; 
         R 4  is alkyl, cycloalkyl, heterocyclyl, or spiroheterocyclyl; wherein the alkyl is optionally substituted with one or more F; 
         R 5  is hydrogen or deuterium; 
         each R 6  is independently selected from CH 3 , spirocyclopropyl and OH; 
         m is 0, 1, 2, 3, 4, 5, or 6; 
         n is 0 or 1; and 
         p is 0, 1, or 2. 
       
     
     
         6 . The method of  claim 1 , wherein the cancer is a hematological malignancy selected from multiple myeloma, leukemia, or lymphoma. 
     
     
         7 . The method of  claim 1 , wherein the hematological malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia, acute monocytic leukemia (AMOL), Hodgkin's lymphomas, and non-Hodgkin's lymphomas such as Burkitt lymphoma, B-cell lymphoma. 
     
     
         8 . The method of  claim 1 , wherein the subject is diagnosed with cancer or hematological malignancy. 
     
     
         9 . The method of  claim 1  wherein administering an effective amount of a Bcl-2 inhibitor in combination with a mitochondrial complex II inhibitor is further in combination with an additional chemotherapy agent. 
     
     
         10 . A method of treating multiple myeloma comprising administering an effective amount of venetoclax in combination with a thenoyltrifluoroacetone or atpenin A5 to a subject in need thereof. 
     
     
         11 . A method of comprising,
 a) isolating a sample of cancer cells from a subject,   b) mixing the sample with mitochondrial complex II, succinate, and ubiquinone; and   c) measuring succinate ubiquinone reductase (SQR) activity providing measured SQR activity.   
     
     
         12 . The method of  claim 11  further comprising diagnosing the subject as sensitive to or in need of a chemotherapy treatment comprising administering a Bcl-2 inhibitor in combination with a mitochondrial complex II inhibitor, if the measured SQR activity is higher than a control level. 
     
     
         13 . The method of  claim 11  further comprising diagnosing the subject as not in need of or would not benefit from a chemotherapy comprising administering Bcl-2 inhibitor in combination with a mitochondrial complex II inhibitor, if the measured SQR activity is lower than a control level. 
     
     
         14 . The method of  claim 11 , further comprising the step of recording the measurements. 
     
     
         15 . The method of  claim 14 , wherein the measurements are recorded in an electronic format. 
     
     
         16 . The method of  claim 12 , further comprising the step of recording the diagnosis. 
     
     
         17 . The method of  claim 16 , wherein the diagnosis is recorded in an electronic format. 
     
     
         18 . The method of  claim 17 , further comprising the step of reporting the measurements or diagnosis to a medical professional, the subject, or representative thereof. 
     
     
         19 . The method of  claim 12 , further comprising administering an effective amount of a combination therapy of Bcl-2 inhibitor in combination with a mitochondrial complex II inhibitor to the subject. 
     
     
         20 . A method of diagnosing and treating multiple myeloma comprising,
 a) isolating a sample of myeloma cells from a subject,   b) mixing the sample with mitochondrial complex II, succinate, and ubiquinone; and   c) measuring succinate ubiquinone reductase (SQR) activity providing measured SQR activity; and   d) treating the subject with venetoclax in combination with thenoyltrifluoroacetone or atpenin A5 if the measured SQR activity is higher than a control level.