Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors

  • J Med Chem. 2016 Sep 22;59(18):8306-25. doi: 10.1021/acs.jmedchem.6b00515.
Pei-Pei Kung ,  Eugene Rui ,  Simon Bergqvist ,  Patrick Bingham ,  John Braganza ,  Michael Collins ,  Mei Cui ,  Wade Diehl ,  Dac Dinh ,  Connie Fan ,  Valeria R Fantin ,  Hovhannes J Gukasyan ,  Wenyue Hu ,  Buwen Huang ,  Susan Kephart ,  Cody Krivacic ,  Robert A Kumpf ,  Gary Li ,  Karen A Maegley ,  Indrawan McAlpine ,  Lisa Nguyen ,  Sacha Ninkovic ,  Martha Ornelas ,  Michael Ryskin  1 ,  Stephanie Scales ,  Scott Sutton ,  John Tatlock ,  Dominique Verhelle ,  Fen Wang ,  Peter Wells ,  Martin Wythes ,  Shinji Yamazaki ,  Brian Yip ,  Xiu Yu ,  Luke Zehnder ,  Wei-Guo Zhang  1 ,  Robert A Rollins  1 ,  Martin Edwards
Affiliations
  • 1. Pfizer Global Research and Development , 401 North Middletown Road, Pearl River, New York 10965, United States.
PMID: 27512831 DOI: 10.1021/acs.jmedchem.6b00515
Abstract

A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.

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