6VIX
BRD4_Bromodomain2 complex with pyrrolopyridone compound 18
Summary for 6VIX
| Entry DOI | 10.2210/pdb6vix/pdb |
| Descriptor | Bromodomain-containing protein 4, 4-[2-(2,4-difluorophenoxy)-5-(methylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (3 entities in total) |
| Functional Keywords | bromodomain, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 53461.94 |
| Authors | Longenecker, K.L.,Park, C.H.,Qiu, W. (deposition date: 2020-01-14, release date: 2020-05-06, Last modification date: 2023-10-11) |
| Primary citation | Sheppard, G.S.,Wang, L.,Fidanze, S.D.,Hasvold, L.A.,Liu, D.,Pratt, J.K.,Park, C.H.,Longenecker, K.,Qiu, W.,Torrent, M.,Kovar, P.J.,Bui, M.,Faivre, E.,Huang, X.,Lin, X.,Wilcox, D.,Zhang, L.,Shen, Y.,Albert, D.H.,Magoc, T.J.,Rajaraman, G.,Kati, W.M.,McDaniel, K.F. Discovery ofN-Ethyl-4-[2-(4-fluoro-2,6-dimethyl-phenoxy)-5-(1-hydroxy-1-methyl-ethyl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (ABBV-744), a BET Bromodomain Inhibitor with Selectivity for the Second Bromodomain. J.Med.Chem., 63:5585-5623, 2020 Cited by PubMed Abstract: The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (∼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound (ABBV-744). PubMed: 32324999DOI: 10.1021/acs.jmedchem.0c00628 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.116 Å) |
Structure validation
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