2. Academic Validation
  3. Discovery and lead identification of quinazoline-based BRD4 inhibitors

Discovery and lead identification of quinazoline-based BRD4 inhibitors

  • Bioorg Med Chem Lett. 2018 Nov 15;28(21):3483-3488. doi: 10.1016/j.bmcl.2018.08.039.
Shyh-Ming Yang 1,  Daniel J Urban 2,  Makoto Yoshioka 3,  Jeffrey W Strovel 3,  Steven Fletcher 4,  Amy Q Wang 2,  Xin Xu 2,  Pranav Shah 2,  Xin Hu 2,  Matthew D Hall 2,  Ajit Jadhav 2,  David J Maloney 5
Affiliations

Affiliations

  • 1 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.
  • 2 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
  • 3 ConverGene LLC., 3093 Beverly Lane, Unit C, Cambridge, MD 21613, United States.
  • 4 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD 21201, United States.
  • 5 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States. Electronic address: dave@NexusDA.com.
PMID: 30268702 DOI: 10.1016/j.bmcl.2018.08.039
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 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.

Keywords

BET inhibitor; BRD4; Bromodomain; Cancer; Inflammation; Quinazoline.

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