Discovery of IHMT-EZH2-115 as a Potent and Selective Enhancer of Zeste Homolog 2 (EZH2) Inhibitor for the Treatment of B-Cell Lymphomas

The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been identified in hematologic malignancies and solid tumors. Based on the structure of EPZ6438 ( 1 ) and the binding model with PRC2, we designed a series of analogues aiming to improve the activities of EZH2 mutants. Structure–activity relationship (SAR) exploration at both enzymatic and cellular levels led to the discovery of inhibitor 29 . In the biochemical assay, 29 inhibited EZH2 (IC 50 = 26.1 nM) with high selectivity over other histone methyltransferases. It was also potent against EZH2 mutants (EZH2 Y641F, IC 50 = 72.3 nM). Furthermore, it showed no apparent inhibitory activity against the human ether-á-go-go related gene (hERG) (IC 50 > 30 μM). In vivo, 29 exhibited favorable pharmacokinetic properties for oral administration and showed better efficacy than 1 in both Pfeiffer and Karpas-422 cell-mediated xenograft mouse models, indicating that it might be a new potential therapeutic candidate for EZH2 mutant cancers.