5D0C

Crystal Structure of the first bromodomain of human BRD4 in complex with benzo[cd]indol-2(1H)-one ligand

5D0C の概要

• エントリーDOI: 10.2210/pdb5d0c/pdb
• 関連するPDBエントリー: 5COI 5CP5 5CPE 5CQT 5CRM 5CRZ 5CS8 5CTL 5CY9
• 分子名称: Bromodomain-containing protein 4, NITRATE ION, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: brd4, bromodomain, four alpha helices, bromodomain binding inhibitor, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17585.08

構造登録者

Zhang, Y.,Song, M.,Liu, Z.,Xue, X.,Xu, Y. (登録日: 2015-08-03, 公開日: 2016-01-13, 最終更新日: 2023-11-29)

主引用文献

Xue, X.,Zhang, Y.,Liu, Z.,Song, M.,Xing, Y.,Xiang, Q.,Wang, Z.,Tu, Z.,Zhou, Y.,Ding, K.,Xu, Y.
Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation
J.Med.Chem., 59:1565-1579, 2016

PubMed Abstract: The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

PubMed: 26731490
DOI: 10.1021/acs.jmedchem.5b01511

実験手法

X-RAY DIFFRACTION (1.49 Å)