6TPY
N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 1,3-dimethyl-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one
This is a non-PDB format compatible entry.
Summary for 6TPY
| Entry DOI | 10.2210/pdb6tpy/pdb |
| Descriptor | Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 1,3-dimethyl-5-[1-(oxan-4-ylmethyl)benzimidazol-2-yl]pyridin-2-one, ... (4 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 | 15623.00 |
| Authors | Chung, C. (deposition date: 2019-12-15, release date: 2020-01-15, Last modification date: 2024-05-01) |
| Primary citation | Wellaway, C.R.,Amans, D.,Bamborough, P.,Barnett, H.,Bit, R.A.,Brown, J.A.,Carlson, N.R.,Chung, C.W.,Cooper, A.W.J.,Craggs, P.D.,Davis, R.P.,Dean, T.W.,Evans, J.P.,Gordon, L.,Harada, I.L.,Hirst, D.J.,Humphreys, P.G.,Jones, K.L.,Lewis, A.J.,Lindon, M.J.,Lugo, D.,Mahmood, M.,McCleary, S.,Medeiros, P.,Mitchell, D.J.,O'Sullivan, M.,Le Gall, A.,Patel, V.K.,Patten, C.,Poole, D.L.,Shah, R.R.,Smith, J.E.,Stafford, K.A.J.,Thomas, P.J.,Vimal, M.,Wall, I.D.,Watson, R.J.,Wellaway, N.,Yao, G.,Prinjha, R.K. Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening. J.Med.Chem., 63:714-746, 2020 Cited by PubMed Abstract: The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize -acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an -methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose. PubMed: 31904959DOI: 10.1021/acs.jmedchem.9b01670 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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