6VIX

BRD4_Bromodomain2 complex with pyrrolopyridone compound 18

6VIX の概要

• エントリーDOI: 10.2210/pdb6vix/pdb
• 分子名称: 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)
• 機能のキーワード: bromodomain, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 53461.94

構造登録者

Longenecker, K.L.,Park, C.H.,Qiu, W. (登録日: 2020-01-14, 公開日: 2020-05-06, 最終更新日: 2023-10-11)

主引用文献

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

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: 32324999
DOI: 10.1021/acs.jmedchem.0c00628

実験手法

X-RAY DIFFRACTION (2.116 Å)