5vom
From Proteopedia
Benzopiperazine BET bromodomain inhibitor in complex with BD1 of Brd4
Structural highlights
Disease[BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2] Function[BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedA 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). Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.,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, McKinnon C ACS Med Chem Lett. 2017 Jul 14;8(8):847-852. doi: 10.1021/acsmedchemlett.7b00191., eCollection 2017 Aug 10. PMID:28835800[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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