Enhancer of Zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2). EZH2 is a histone methyltransferase, methylating histone 3 at lysine 27 (H3K27). Since aberrations in EZH2 function via mutation, expression, or other changes to chromatin remodeling pathways are common in many cancers, direct inhibitors of EZH2 and other modulators of PRC2 complex activity are desired as potential anticancer treatments.<br/><br/>The earliest reports of EZH2 inhibitors described a 4,6,7-trisubstituted pyridone as a central element of the pharmacophore, as exemplified by the clinical compound tazemetostat. Over time, this pyridone fragment has been incorporated by many into several novel series of EZH2 inhibitors, typically with little to no variation of its 4,6-dimethyl substitution pattern.<br/><br/>We utilized the published structures of the PRC2 complex to design novel EZH2 inhibitors employing heterobicyclic derivatives of the pyridone. As shown by the exemplar in the figure, these pyridone derivatives afforded analogs with low nanomolar potencies against EZH2. The structure-based drug design, synthesis and SAR of these bicyclic series of analogs will be described.

Discovery of novel bicyclic pyridone derivatives as inhibitors of EZH2

255th National Meeting (2018)

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