5KDH

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH A DIHYDROPYRIDOPYRIMIDINE SCAFFOLD INHIBITOR

5KDH の概要

• エントリーDOI: 10.2210/pdb5kdh/pdb
• 関連するPDBエントリー: 5KJ0
• 分子名称: Bromodomain-containing protein 4, (5~{S})-1-ethyl-5-(4-methylphenyl)-8,9-dihydro-5~{H}-furo[3,4]pyrido[3,5-~{b}]pyrimidine-2,4,6-trione, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: bromodomain, cap, hunk1, mcap, protein binding-inhibitor complex, mitotic chromosome associated protein, cell cycle, inhibitor, transcription-inhibitor complex, transcription/inhibitor
• 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: 15692.92

構造登録者

Zhu, J.-Y.,Schonbrunn, E. (登録日: 2016-06-08, 公開日: 2017-08-02, 最終更新日: 2023-09-27)

主引用文献

Ayoub, A.M.,Hawk, L.M.L.,Herzig, R.J.,Jiang, J.,Wisniewski, A.J.,Gee, C.T.,Zhao, P.,Zhu, J.Y.,Berndt, N.,Offei-Addo, N.K.,Scott, T.G.,Qi, J.,Bradner, J.E.,Ward, T.R.,Schonbrunn, E.,Georg, G.I.,Pomerantz, W.C.K.
BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.
J. Med. Chem., 60:4805-4817, 2017

PubMed Abstract: Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.

PubMed: 28535045
DOI: 10.1021/acs.jmedchem.6b01336

実験手法

X-RAY DIFFRACTION (1.5 Å)