6S55

Crystal structure of human ATAD2 bromodomain in complex with N-(4-bromo-3-((3-methylpiperidin-1-yl)sulfonyl)phenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetamide

6S55 の概要

• エントリーDOI: 10.2210/pdb6s55/pdb
• 分子名称: ATPase family AAA domain-containing protein 2, 1,2-ETHANEDIOL, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, atad2, bromodomain, epigenetics, atpase family aaa domain-containing protein 2, 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: 16243.12

構造登録者

Chung, C. (登録日: 2019-06-30, 公開日: 2019-08-21, 最終更新日: 2024-05-15)

主引用文献

Bamborough, P.,Chung, C.W.,Demont, E.H.,Bridges, A.M.,Craggs, P.D.,Dixon, D.P.,Francis, P.,Furze, R.C.,Grandi, P.,Jones, E.J.,Karamshi, B.,Locke, K.,Lucas, S.C.C.,Michon, A.M.,Mitchell, D.J.,Pogany, P.,Prinjha, R.K.,Rau, C.,Roa, A.M.,Roberts, A.D.,Sheppard, R.J.,Watson, R.J.
A Qualified Success: Discovery of a New Series of ATAD2 Bromodomain Inhibitors with a Novel Binding Mode Using High-Throughput Screening and Hit Qualification.
J.Med.Chem., 62:7506-7525, 2019

PubMed Abstract: The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.

PubMed: 31398032
DOI: 10.1021/acs.jmedchem.9b00673

実験手法

X-RAY DIFFRACTION (2.09 Å)