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