8PXA
N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH (S)-5-(1-((1-(1-isopropylpiperidine-4-carbonyl)piperidin-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one
This is a non-PDB format compatible entry.
Summary for 8PXA
| Entry DOI | 10.2210/pdb8pxa/pdb |
| Related | 8PX2 8PX8 |
| Descriptor | Bromodomain-containing protein 4, 1,3-dimethyl-5-[1-[[(3~{S})-1-(1-propan-2-ylpiperidin-4-yl)carbonylpiperidin-3-yl]methyl]benzimidazol-2-yl]pyridin-2-one (3 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 | 15589.03 |
| Authors | Chung, C. (deposition date: 2023-07-22, release date: 2023-10-18, Last modification date: 2023-12-27) |
| Primary citation | Bradley, E.,Fusani, L.,Chung, C.W.,Craggs, P.D.,Demont, E.H.,Humphreys, P.G.,Mitchell, D.J.,Phillipou, A.,Rioja, I.,Shah, R.R.,Wellaway, C.R.,Prinjha, R.K.,Palmer, D.S.,Kerr, W.J.,Reid, M.,Wall, I.D.,Cookson, R. Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe. J.Med.Chem., 66:15728-15749, 2023 Cited by PubMed Abstract: Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition. PubMed: 37967462DOI: 10.1021/acs.jmedchem.3c00906 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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