6FFG

Human BRD2 C-terminal bromodomain with (S)-1-(2-cyclopropyl-4-(2-(hydroxymethyl)benzyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone

Summary for 6FFG

• Entry DOI: 10.2210/pdb6ffg/pdb
• Related: 6FFD 6FFE 6FFF
• Descriptor: Bromodomain-containing protein 2, 1,2-ETHANEDIOL, (S)-1-(2-cyclopropyl-4-(2-(hydroxymethyl)benzyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethanone, ... (6 entities in total)
• Functional Keywords: inhibitor, histone, epigenetic reader, bromodomain, brd4, bromodomain containing protein 4, antagonist, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 14381.62

Authors

Chung, C. (deposition date: 2018-01-07, release date: 2019-01-30, Last modification date: 2024-05-08)

Primary citation

Law, R.P.,Atkinson, S.J.,Bamborough, P.,Chung, C.W.,Demont, E.H.,Gordon, L.J.,Lindon, M.,Prinjha, R.K.,Watson, A.J.B.,Hirst, D.J.
Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain.
J.Med.Chem., 61:4317-4334, 2018

PubMed Abstract: The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.

PubMed: 29656650
DOI: 10.1021/acs.jmedchem.7b01666

Experimental method

X-RAY DIFFRACTION (1.59 Å)