Details

Autor(en) / Beteiligte

• Kung, Pei-Pei
• Rui, Eugene
• Bergqvist, Simon
• Bingham, Patrick
• Braganza, John
• Collins, Michael
• Cui, Mei
• Diehl, Wade
• Dinh, Dac
• Fan, Connie
• Fantin, Valeria R
• Gukasyan, Hovhannes J
• Hu, Wenyue
• Huang, Buwen
• Kephart, Susan
• Krivacic, Cody
• Kumpf, Robert A
• Li, Gary
• Maegley, Karen A
• McAlpine, Indrawan
• Nguyen, Lisa
• Ninkovic, Sacha
• Ornelas, Martha
• Ryskin, Michael
• Scales, Stephanie
• Sutton, Scott
• Tatlock, John
• Verhelle, Dominique
• Wang, Fen
• Wells, Peter
• Wythes, Martin
• Yamazaki, Shinji
• Yip, Brian
• Yu, Xiu
• Zehnder, Luke
• Zhang, Wei-Guo
• Rollins, Robert A
• Edwards, Martin

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2016-09, Vol.59 (18), p.8306-8325

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.