6P38

Crystal Structure Analysis of TAF1 Bromodomain

6P38 の概要

• エントリーDOI: 10.2210/pdb6p38/pdb
• 分子名称: Transcription initiation factor TFIID subunit 1, 4-{[(3R)-4-cyclopentyl-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl]amino}-N-(1-methylpiperidin-4-yl)-3-[(propan-2-yl)oxy]benzamide (2 entities in total)
• 機能のキーワード: kinase, bromodomain, inhibitor, transcription, transferase
• 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: 16417.51

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2019-05-23, 公開日: 2020-05-27, 最終更新日: 2023-10-11)

主引用文献

Remillard, D.,Buckley, D.L.,Seo, H.S.,Ferguson, F.M.,Dhe-Paganon, S.,Bradner, J.E.,Gray, N.S.
Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold.
Acs Med.Chem.Lett., 10:1443-1449, 2019

PubMed Abstract: Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.

PubMed: 31620231
DOI: 10.1021/acsmedchemlett.9b00243

実験手法

X-RAY DIFFRACTION (2.8 Å)