6X7C

BRD4 Bromodomain 1 in complex with multi-action inhibitor SRX3212

6X7C の概要

• エントリーDOI: 10.2210/pdb6x7c/pdb
• 分子名称: Bromodomain-containing protein 4, 7-[5-(morpholin-4-yl)-7-oxo-7H-thieno[3,2-b]pyran-3-yl]-N-[(pyridin-3-yl)methyl]-2,3-dihydro-1,4-benzodioxine-5-carboxamide (3 entities in total)
• 機能のキーワード: brd4, pi3k, cdk4/6, 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: 16359.79

構造登録者

Vann, K.R.,Kutateladze, T.G. (登録日: 2020-05-29, 公開日: 2020-08-05, 最終更新日: 2023-10-18)

主引用文献

Vann, K.R.,Pal, D.,Morales, G.A.,Burgoyne, A.M.,Durden, D.L.,Kutateladze, T.G.
Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.
Sci Rep, 10:12027-12027, 2020

PubMed Abstract: Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes.

PubMed: 32694708
DOI: 10.1038/s41598-020-68964-6

実験手法

X-RAY DIFFRACTION (2.7 Å)