4C66

Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains

Summary for 4C66

• Entry DOI: 10.2210/pdb4c66/pdb
• Related: 4C67
• Descriptor: BROMODOMAIN-CONTAINING PROTEIN 4, 4-(2-chlorophenyl)-2-ethyl-9-methyl-6,8-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium (3 entities in total)
• Functional Keywords: cell cycle, transcription regulation, inhibitor, epigenetic reader, antagonist
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15314.12

Authors

Chung, C.,Mirguet, O. (deposition date: 2013-09-17, release date: 2013-10-02, Last modification date: 2024-05-08)

Primary citation

Mirguet, O.,Gosmini, R.,Toum, J.,Clement, C.,Barnathan, M.,Brusq, J.,Mordaunt, J.E.,Grimes, R.,Crowe, M.,Pineau, O.,Ajakane, M.,Daugan, A.,Jeffrey, P.,Cutler, L.,Haynes, A.,Smithers, N.,Chung, C.,Bamborough, P.,Uings, I.J.,Lewis, T.,Witherington, J.,Parr, N.,Prinjha, R.,Nicodeme, E.
Discovery of Epigenetic Regulator I-Bet762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the Bet Bromodomains.
J.Med.Chem., 56:7501-, 2013

PubMed Abstract: The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.

PubMed: 24015967
DOI: 10.1021/JM401088K

Experimental method

X-RAY DIFFRACTION (1.87 Å)