1. Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors.
- Author
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Bennett MJ, Wu Y, Boloor A, Matuszkiewicz J, O'Connell SM, Shi L, Stansfield RK, Del Rosario JR, Veal JM, Hosfield DJ, Xu J, Kaldor SW, Stafford JA, and Betancort JM
- Subjects
- Binding Sites, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival drug effects, Crystallography, X-Ray, Humans, Inhibitory Concentration 50, Isoquinolines chemical synthesis, Isoquinolines pharmacology, Molecular Dynamics Simulation, Nuclear Proteins metabolism, Protein Structure, Tertiary, Structure-Activity Relationship, Transcription Factors metabolism, Drug Design, Isoquinolines chemistry, Nuclear Proteins antagonists & inhibitors, Transcription Factors antagonists & inhibitors
- 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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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