title: Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors.
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.
authors: Pei-Pei
authors: PP
authors: Kung
authors: Eugene
authors: E
authors: Rui
authors: Simon
authors: S
authors: Bergqvist
authors: Patrick
authors: P
authors: Bingham
authors: John
authors: J
authors: Braganza
authors: Michael
authors: M
authors: Collins
authors: Mei
authors: M
authors: Cui
authors: Wade
authors: W
authors: Diehl
authors: Dac
authors: D
authors: Dinh
authors: Connie
authors: C
authors: Fan
authors: Valeria R
authors: VR
authors: Fantin
authors: Hovhannes J
authors: HJ
authors: Gukasyan
authors: Wenyue
authors: W
authors: Hu
authors: Buwen
authors: B
authors: Huang
authors: Susan
authors: S
authors: Kephart
authors: Cody
authors: C
authors: Krivacic
authors: Robert A
authors: RA
authors: Kumpf
authors: Gary
authors: G
authors: Li
authors: Karen A
authors: KA
authors: Maegley
authors: Indrawan
authors: I
authors: McAlpine
authors: Lisa
authors: L
authors: Nguyen
authors: Sacha
authors: S
authors: Ninkovic
authors: Martha
authors: M
authors: Ornelas
authors: Pfizer Global Research and Development , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors: Michael
authors: M
authors: Ryskin
authors: Stephanie
authors: S
authors: Scales
authors: Scott
authors: S
authors: Sutton
authors: John
authors: J
authors: Tatlock
authors: Dominique
authors: D
authors: Verhelle
authors: Fen
authors: F
authors: Wang
authors: Peter
authors: P
authors: Wells
authors: Martin
authors: M
authors: Wythes
authors: Shinji
authors: S
authors: Yamazaki
authors: Brian
authors: B
authors: Yip
authors: Xiu
authors: X
authors: Yu
authors: Luke
authors: L
authors: Zehnder
authors: Pfizer Global Research and Development , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors: Wei-Guo
authors: WG
authors: Zhang
authors: Pfizer Global Research and Development , 401 North Middletown Road, Pearl River, New York 10965, United States.
authors: Robert A
authors: RA
authors: Rollins
authors: Martin
authors: M
authors: Edwards
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003500:Cyclization; D015195:Drug Design; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C459809:1,5-dihydroisoquinoline; D000970:Antineoplastic Agents; D007546:Isoquinolines; D007769:Lactams; D011728:Pyridones; D000071221:Enhancer of Zeste Homolog 2 Protein