1. Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains
- Author
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Grace L. Williams, Shawn Schiller, Monica A. Alvarez Morales, Crystal McKinnon, Matthew W. Martin, George P. Luke, Torsten Herbertz, Adam C. Talbot, Stephen Hubbs, Katherine J. Kayser-Bricker, Daniel Cardillo, Paul Troccolo, David S. Millan, and Rachel L. Mendes
- Subjects
0301 basic medicine ,Cellular activity ,Chemistry ,Organic Chemistry ,A protein ,Biochemistry ,Combinatorial chemistry ,Small molecule ,Bromodomain ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Mouse xenograft ,In vivo ,Lipophilic efficiency ,030220 oncology & carcinogenesis ,Drug Discovery ,Binding site - 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).
- Published
- 2017