Discovery and lead identification of quinazoline-based BRD4 inhibitors.
Shyh-Ming Yang, Daniel J Urban, Makoto Yoshioka, Jeffrey W Strovel, Steven Fletcher, Amy Q Wang, Xin Xu, Pranav Shah, Xin Hu, Matthew D Hall, Ajit Jadhav, David J Maloney
Author Information
Shyh-Ming Yang: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States. Electronic address: yangs9@mail.nih.gov.
Daniel J Urban: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Makoto Yoshioka: ConverGene LLC., 3093 Beverly Lane, Unit C, Cambridge, MD 21613, United States.
Jeffrey W Strovel: ConverGene LLC., 3093 Beverly Lane, Unit C, Cambridge, MD 21613, United States.
Steven Fletcher: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD 21201, United States.
Amy Q Wang: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Xin Xu: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Pranav Shah: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Xin Hu: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Matthew D Hall: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Ajit Jadhav: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
David J Maloney: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States. Electronic address: dave@NexusDA.com.
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 of 48 (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.
