4UYH

N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-((2R,4S)-2-methyl-4-(phenylamino)-6-(4-(piperidin-1-ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

4UYH の概要

• エントリーDOI: 10.2210/pdb4uyh/pdb
• 関連するPDBエントリー: 4UYD 4UYE 4UYF 4UYG
• 分子名称: BROMODOMAIN-CONTAINING PROTEIN 2, 1-[(2S,4R)-2-methyl-4-(phenylamino)-6-[4-(piperidin-1-ylmethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl]ethanone, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: transcription, histone, epigenetic reader, bet, brd2, bromodomain
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 54807.61

構造登録者

Chung, C.,Bamborough, P.,Gosmini, R. (登録日: 2014-08-31, 公開日: 2014-10-08, 最終更新日: 2024-05-08)

主引用文献

Gosmini, R.,Nguyen, V.L.,Toum, J.,Simon, C.,Brusq, J.M.,Krysa, G.,Mirguet, O.,Riou-Eymard, A.M.,Boursier, E.V.,Trottet, L.,Bamborough, P.,Clark, H.,Chung, C.W.,Cutler, L.,Demont, E.H.,Kaur, R.,Lewis, A.J.,Schilling, M.B.,Soden, P.E.,Taylor, S.,Walker, A.L.,Walker, M.D.,Prinjha, R.K.,Nicodeme, E.
The Discovery of I-Bet726 (Gsk1324726A), a Potent Tetrahydroquinoline Apoa1 Up-Regulator and Selective Bet Bromodomain Inhibitor.
J.Med.Chem., 57:8111-, 2014

PubMed Abstract: Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

PubMed: 25249180
DOI: 10.1021/JM5010539

実験手法

X-RAY DIFFRACTION (1.73 Å)