Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors. Issue 10 (1st June 2018)

• Record Type: Journal Article
• Authors: Bennett, Michael J.; Wu, Yiqin; Boloor, Amogh; Matuszkiewicz, Jennifer; O'Connell, Shawn M.; Shi, Lihong; Stansfield, Ryan K.; Del Rosario, Joselyn R.; Veal, James M.; Hosfield, David J.; Xu, Jiangchun; Kaldor, Stephen W.; Stafford, Jeffrey A.; Betancort, Juan M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 10(2018)
• Page Start: 1811
• Page End: 1816
• Publication Date: 2018-06-01
• Subjects: Epigenetics -- Bromodomain inhibitors -- BET -- BRD4 -- Fragment -- Isoquinolinone; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.04.016
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Novel 4-phenylisoquinolinone BET bromodomain inhibitors are disclosed. Structure guided SAR exploration resulted in >10, 000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Abstract: The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10, 000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.