Discovery and lead identification of quinazoline-based BRD4 inhibitors. Issue 21 (15th November 2018)

• Record Type: Journal Article
• Authors: Yang, Shyh-Ming; Urban, Daniel J.; Yoshioka, Makoto; Strovel, Jeffrey W.; Fletcher, Steven; Wang, Amy Q.; Xu, Xin; Shah, Pranav; Hu, Xin; Hall, Matthew D.; Jadhav, Ajit; Maloney, David J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 21(2018)
• Page Start: 3483
• Page End: 3488
• Publication Date: 2018-11-15
• Subjects: BET inhibitor -- BRD4 -- Bromodomain -- Quinazoline -- Cancer -- Inflammation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.08.039
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Quinazoline can serve as a novel core structure in the design of potent BRD4 inhibitors. N -Methyl 2-pyridone is a viable alternative to 3, 5-dimethylisoxazole. Combination of pyrazole and phenylmorpholine substitutions improved pharmacokinetics. Abstract: A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.