5VOM

Benzopiperazine BET bromodomain inhibitor in complex with BD1 of Brd4

Summary for 5VOM

• Entry DOI: 10.2210/pdb5vom/pdb
• Descriptor: Bromodomain-containing protein 4, 3-[(2S)-1-acetyl-4-(furan-2-carbonyl)-2-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl]-N-methylbenzamide (3 entities in total)
• Functional Keywords: bromodomain brd4 bet benzopiperazine, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 2
• Total formula weight: 36084.99

Authors

Toms, A.V.,Herbertz, T. (deposition date: 2017-05-03, release date: 2017-08-02, Last modification date: 2024-03-13)

Primary citation

Millan, D.S.,Kayser-Bricker, K.J.,Martin, M.W.,Talbot, A.C.,Schiller, S.E.R.,Herbertz, T.,Williams, G.L.,Luke, G.P.,Hubbs, S.,Alvarez Morales, M.A.,Cardillo, D.,Troccolo, P.,Mendes, R.L.,McKinnon, C.
Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.
ACS Med Chem Lett, 8:847-852, 2017

PubMed 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 , which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).

PubMed: 28835800
DOI: 10.1021/acsmedchemlett.7b00191

Experimental method

X-RAY DIFFRACTION (1.67 Å)