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Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.

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).

SUBMITTER: Millan DS

PROVIDER: S-EPMC5554895 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.

Millan David S DS Kayser-Bricker Katherine J KJ Martin Matthew W MW Talbot Adam C AC Schiller Shawn E R SER Herbertz Torsten T Williams Grace L GL Luke George P GP Hubbs Stephen S Alvarez Morales Monica A MA Cardillo Daniel D Troccolo Paul P Mendes Rachel L RL McKinnon Crystal C

ACS medicinal chemistry letters 20170714 8

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 physi ...[more]

PMID: 28835800

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