jm6b00515_si_001.pdf (1007.93 kB)

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

Download (1007.93 kB)
journal contribution
posted on 11.08.2016, 00:00 by 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, 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, Robert A. Rollins, Martin Edwards
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.