2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors

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

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: jbetancort@celgene.com.
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.

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