Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma

MutationswithinthecatalyticdomainofthehistonemethyltransferaseEZH2havebeenidentifiedinsubsets of patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We have previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2. Although both compounds are similar with respect to their mechanism of action and selectivity, EPZ-6438 possesses superior potency and drug-like properties, including good oral bioavailability in animals. Here, we characterize the activity of EPZ-6438 in preclinical models of NHL. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration- and time-dependent mannerin bothEZH2wild-type andmutant lymphoma cells. Inhibition of H3K27trimethylation (H3K27Me3) leads to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. TreatmentofEZH2-mutantNHLxenograft-bearingmicewithEPZ-6438causesdose-dependenttumorgrowth inhibition, including complete and sustained tumor regressions with correlative diminution of H3K27Me3 levelsintumorsandselectednormaltissues.MicedosedorallywithEPZ-6438for28daysremainedtumorfree for up to 63 days after stopping compound treatment in two EZH2-mutant xenograft models. These data confirm the dependency of EZH2-mutant NHL on EZH2 activity and portend the utility of EPZ-6438 as a potential treatment for these genetically defined cancers. Mol Cancer Ther; 13(4); 842–54. � 2014 AACR.