The EZH2 histone methyltransferase is a member of the Polycomb Repressor Complex 2 and initiates long-term gene silencing by methylating lysine 27 on histone H3 (H3K27). The high H3K27me3 levels in diffuse large B-cell lymphoma (DLBCL) cell lines harboring Y641 and A677 mutations suggest a high enzymatic activity for the PRC2 complex. This phenotype also suggests that inhibition of EZH2 methyltransferase activity using small molecules may represent a novel therapeutic strategy for treating cancer patients with DLBCL.Our internal research program seeks small molecule inhibitors that can inhibit the EZH2 SET domain catalytic function and therefore reduce the formation of trimethylated H3K27. We developed a robust biochemical assay to measure blocking the transfer of the tritium-containing methyl group from the SAM EZH2 co-factor to the histone 3 lysine 27 residue of the nucleosome isolated from the Hela cells. The common EZH2 inhibitor pharmacophore reported in the literature contains a dimethylpyridone moiety coupled to a variety of aromatic residues. We therefore started our lead finding effort by incorporating this important pharmacophore into a molecule containing a simple phenyl carboxyamide (compound A). In this presentation, we report the SAR we developed in this benzamide series and the optimization process that was used to improve the potency and lipophilic efficiency (LipE) of the initial lead. This medchem optimization process rendered a promising compound (MP lead) which displayed improved potency and LipE compared with the initial lead (compound A). MP lead is a selective and SAM competitive EZH2 inhibitor. MP lead demonstrated a dose-dependent tumor growth inhibition in female scid-beige mice subcutaneously implanted with Karpas422 cells. Further optimization of MP lead is warranted to further improve its potency and PK profile.

Identification of novel benzamide-pyridone-containing EZH2 inhibitors

248th National Meeting (2014)

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