1. Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors
- Author
-
Lihong Shi, Jiangchun Xu, A. Boloor, Stephen W. Kaldor, David J. Hosfield, J.M. Betancort, Jennifer Matuszkiewicz, James M. Veal, M.J. Bennett, Ryan Stansfield, Shawn M. O'Connell, Jeffrey A. Stafford, J.R. Del Rosario, and Y. Wu
- Subjects
0301 basic medicine ,BRD4 ,Cell Survival ,Clinical Biochemistry ,Pharmaceutical Science ,Cell Cycle Proteins ,Computational biology ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Biochemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,Cell Line, Tumor ,Drug Discovery ,Humans ,Structure–activity relationship ,Epigenetics ,Molecular Biology ,Transcription factor ,Binding Sites ,Drug discovery ,Chemistry ,Organic Chemistry ,Nuclear Proteins ,Isoquinolines ,Small molecule ,Protein Structure, Tertiary ,Bromodomain ,030104 developmental biology ,Drug Design ,Molecular Medicine ,Pharmacophore ,Transcription Factors - 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.
- Published
- 2018