Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors

  • Bioorg Med Chem Lett. 2018 Jun 1;28(10):1811-1816. doi: 10.1016/j.bmcl.2018.04.016.
Michael J Bennett  1 ,  Yiqin Wu  1 ,  Amogh Boloor  1 ,  Jennifer Matuszkiewicz  1 ,  Shawn M O'Connell  1 ,  Lihong Shi  1 ,  Ryan K Stansfield  1 ,  Joselyn R Del Rosario  1 ,  James M Veal  1 ,  David J Hosfield  2 ,  Jiangchun Xu  1 ,  Stephen W Kaldor  1 ,  Jeffrey A Stafford  1 ,  Juan M Betancort  3
Affiliations
  • 1. Celgene Quanticel Research, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, United States.
  • 2. Ben May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, IL 60637, United States.
  • 3. Celgene Quanticel Research, 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, United States. Electronic address: [email protected].
PMID: 29657099 DOI: 10.1016/j.bmcl.2018.04.016
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.

Keywords
BET; BRD4; Bromodomain inhibitors; Epigenetics; Fragment; Isoquinolinone.