Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth

The histone methyltransferase enhancer of Zeste homolog 2 (EZH2) is a candidate oncogene due to its prevalent overexpression in malignant diseases, including late stage prostate and breast cancers. The dependency of cancer cells on EZH2 activity is also predicated by recurrent missense mutations residing in the catalytic domain of EZH2 that have been identified in subtypes of diffuse large B cell lymphoma, follicular lymphoma and melanoma. Herein, we report the identification of a highly selective small molecule inhibitor series of EZH2 and EZH1. These compounds inhibit wild-type and mutant versions of EZH2 with nanomolar potency, suppress global histone H3-lysine 27 methylation, affect gene expression, and cause selective proliferation defects. These compounds represent a structurally distinct EZH2 inhibitor chemotype for the exploration of the role of Polycomb Repressive Complex 2-mediated H3K27 methylation in various biological contexts. [Display omitted] •Discovery of potent and selective EZH2 and EZH1 small molecule inhibitors•Selective cell killing of DLBCL cells harboring a heterozygous EZH2 mutation•Inhibitor affects global histone H3 lysine 27 di- and tri-, but less monomethylation•EZH2 inhibitor affects gene expression in DLBCL cells Garapaty-Rao et al. report the discovery and optimization of the histone lysine methyltransferases EZH2 and EZH1 inhibitor. The inhibitor reduces global histone H3K27 di- and trimethylation, induces specific transcriptional programs, and selectively kills lymphoma cells in a dose- and time-dependent manner.