1. Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.
- Author
-
Millan DS, Kayser-Bricker KJ, Martin MW, Talbot AC, Schiller SER, Herbertz T, Williams GL, Luke GP, Hubbs S, Alvarez Morales MA, Cardillo D, Troccolo P, Mendes RL, and McKinnon C
- 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
- Full Text
- View/download PDF