2. Academic Validation
  3. Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains

Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains

  • ACS Med Chem Lett. 2017 Jul 14;8(8):847-852. doi: 10.1021/acsmedchemlett.7b00191.
David S Millan 1,  Katherine J Kayser-Bricker 2,  Matthew W Martin 1,  Adam C Talbot 2,  Shawn E R Schiller 1,  Torsten Herbertz 1,  Grace L Williams 1,  George P Luke 2,  Stephen Hubbs 2,  Monica A Alvarez Morales 1,  Daniel Cardillo 1,  Paul Troccolo 1,  Rachel L Mendes 1,  Crystal McKinnon 1
Affiliations

Affiliations

  • 1 FORMA Therapeutics Inc., 500 Arsenal Street, Suite 100, Watertown, Massachusetts 02472, United States.
  • 2 FORMA Therapeutics Inc., 35 Northeast Industrial Road, Branford, Connecticut 06405, United States.
PMID: 28835800 DOI: 10.1021/acsmedchemlett.7b00191
Abstract

A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound FT001, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).

Keywords

BET; BRD4; Bromodomains.

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