Cancer genomes are characterized by aberrant patterns of DNA and histone modifications. The epigenetic modifiers in many cancer types often exhibit de-regulated expression or genetic mutations. The histone methyltransferase EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of the polycomb repressor complex 2 (PRC2). The PRC2 complex is a highly conserved protein complex that regulates gene expression by methylating lysine 27 residues on histone H3 proteins. EZH2 over-expression and gain-of-function mutations have been identified in both hematological malignancies and solid tumors. The discovery of catalytic inhibitors of EZH2 has provided an invaluable tool for further elucidating the role of this enzyme in cancers. Accordingly, we conducted parallel synthesis using a key EZH2 inhibitor pharmacophore that was reported in the literature. Utilizing conformational analysis and property-based design approaches, we identified a development compound, PF-06821497. A co-crystal structure of PF-06821497 together with several co-crystal structures of the inhibitors in complex with the EZH2-EED-SUZ12 three protein complex were obtained during the course of these activities. The design strategies that led to the identification of the development compound and structure-guided rationalizations of observed potency trends will be presented.

Structural rationalization of bioactivity trends that led to identification of the EZH2 development candidate (PF-06821497)

256th National Meeting (2018)

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