Inhibitors of human ezh2, and methods of use thereof

Abstract

The invention relates to inhibition of wild-type and certain mutant forms of human histone methyltransferase EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27). In one embodiment the inhibition is selective for the mutant form of the EZH2, such that trimethylation of H3-K27, which is associated with certain cancers, is inhibited. The methods can be used to treat cancers including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). Also provided are methods for identifying small molecule selective inhibitors of the mutant forms of EZH2 and also methods for determining responsiveness to an EZH2 inhibitor in a subject.

1 . A method for treating cancer in a subject, comprising administering a therapeutically effective amount of an inhibitor of EZH2 to the subject, where in the subject has been identified as expressing a mutant Enhancer of Zeste Homolog 2 (EZH2) comprising a mutation in the EZH2 SET domain of SEQ ID NO: 6. 
     
     
         2 . The method of  claim 1 , wherein said subject has a cancer selected from leukemia, melanoma, and lymphoma, or is at risk of developing a cancer selected from leukemia, melanoma, and lymphoma. 
     
     
         3 . The method of  claim 2 , wherein said lymphoma is selected from the group consisting of Non-Hodgkin's lymphoma, follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B cell-like (GCB) subtype. 
     
     
         4 . The method of  claim 1 , wherein the mutation in the EZH2 SET domain of SEQ ID NO: 6 is a mutation at position Tyr641 (Y641) of EZH2. 
     
     
         5 . The method of  claim 4 , wherein the mutation at Y641 is selected from the group consisting of Y641F, Y641H, Y641N and Y641S. 
     
     
         6 . The method of  claim 1 , wherein inhibition of EZH2 is selective inhibition. 
     
     
         7 . The method of  claim 1 , wherein the inhibitor of EZH2 inhibits histone methyltransferase activity of wild-type EZH2. 
     
     
         8 . The method  claim 1 , wherein the inhibitor of EZH2 is a small molecule. 
     
     
         9 . A method for treating lymphoma in a subject, comprising administering a therapeutically effective amount of an inhibitor of EZH2 to the subject, where in the subject has been identified as expressing a mutant Enhancer of Zeste Homolog 2 (EZH2) comprising a mutation in the EZH2 SET domain of SEQ ID NO: 6. 
     
     
         10 . The method of  claim 9 , wherein said lymphoma is selected from the group consisting of Non-Hodgkin's lymphoma, follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B cell-like (GCB) subtype. 
     
     
         11 . The method of  claim 9 , wherein the mutation in the EZH2 SET domain of SEQ ID NO: 6 is a mutation at position Tyr641 (Y641) of EZH2. 
     
     
         12 . The method of  claim 9 , wherein the mutation at Y641 is selected from the group consisting of Y641F, Y641H, Y641N and Y641S. 
     
     
         13 . The method of  claim 9 , wherein inhibition of EZH2 is selective inhibition. 
     
     
         14 . The method of  claim 9 , wherein the inhibitor of EZH2 inhibits histone methyltransferase activity of wild-type EZH2. 
     
     
         15 . The method  claim 9 , wherein the inhibitor of EZH2 is a small molecule. 
     
     
         16 . A method for treating cancer in a subject, comprising administering a therapeutically effective amount of an inhibitor of EZH2 to the subject, where in the subject has been identified as expressing at least one mutation in a nucleic acid sample from the subject that comprises at least a portion of SEQ ID NO: 7 or the sequence complementary to SEQ ID NO: 7. 
     
     
         17 . The method of  claim 16 , wherein said subject has a cancer selected from leukemia, melanoma, and lymphoma, or is at risk of developing a cancer selected from leukemia, melanoma, and lymphoma. 
     
     
         18 . The method of  claim 17 , wherein said subject has lymphoma selected from the group consisting of Non-Hodgkin's lymphoma, follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B cell-like (GCB) subtype. 
     
     
         19 . The method of  claim 16 , wherein the at least one mutation comprises a mutation at the nucleotides encoding Y641 in the nucleic acid sample. 
     
     
         20 . The method of  claim 16 , wherein the inhibitor of EZH2 inhibits histone methyltransferase activity of wild-type EZH2.