6HDQ

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH : 8-(((1R,2R,3R,5S)-2-(2-(4,4-difluorocyclohexyl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one

6HDQ の概要

• エントリーDOI: 10.2210/pdb6hdq/pdb
• 分子名称: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 8-(((1R,2R,3R,5S)-2-(2-(4,4-difluorocyclohexyl)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one, ... (4 entities in total)
• 機能のキーワード: inhibitor, histone, epigenetic reader, bromodomain, brd4, bromodomain containing protein 4, antagonist, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15683.09

構造登録者

Chung, C. (登録日: 2018-08-18, 公開日: 2018-09-26, 最終更新日: 2024-05-15)

主引用文献

Bamborough, P.,Chung, C.W.,Furze, R.C.,Grandi, P.,Michon, A.M.,Watson, R.J.,Mitchell, D.J.,Barnett, H.,Prinjha, R.K.,Rau, C.,Sheppard, R.J.,Werner, T.,Demont, E.H.
Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors.
J. Med. Chem., 61:8321-8336, 2018

PubMed Abstract: ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.

PubMed: 30226378
DOI: 10.1021/acs.jmedchem.8b00862

実験手法

X-RAY DIFFRACTION (1.7 Å)