7EVJ

Crystal structure of CBP bromodomain liganded with 9c

7EVJ の概要

• エントリーDOI: 10.2210/pdb7evj/pdb
• 分子名称: CREB-binding protein, 3-acetyl-1-((3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-fluoro-5-(hydroxymethyl)phenyl)carbamoyl)indolizin-7-yl dimethylcarbamate, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: histone acetyltransferase, cbp, bromodomain, protein binding
• 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: 16597.89

構造登録者

Xiang, Q.,Wang, C.,Wu, T.,Zhang, Y.,Zhang, C.,Luo, G.,Wu, X.,Shen, H.,Xu, Y. (登録日: 2021-05-21, 公開日: 2022-02-16, 最終更新日: 2023-11-29)

主引用文献

Xiang, Q.,Wang, C.,Wu, T.,Zhang, C.,Hu, Q.,Luo, G.,Hu, J.,Zhuang, X.,Zou, L.,Shen, H.,Wu, X.,Zhang, Y.,Kong, X.,Liu, J.,Xu, Y.
Design, Synthesis, and Biological Evaluation of 1-(Indolizin-3-yl)ethan-1-ones as CBP Bromodomain Inhibitors for the Treatment of Prostate Cancer.
J.Med.Chem., 65:785-810, 2022

PubMed Abstract: CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound (Y08284), which possesses good liver microsomal stability and pharmacokinetic properties ( = 25.9%). Furthermore, the compound is able to inhibit CBP bromodomain as well as the proliferation, colony formation, and migration of prostate cancer cells. Additionally, the new inhibitor shows promising antitumor efficacy in a 22Rv1 xenograft model (TGI = 88%). This study provides new lead compounds for further development of drugs for the treatment of prostate cancer.

PubMed: 34962793
DOI: 10.1021/acs.jmedchem.1c01864

実験手法

X-RAY DIFFRACTION (2.57 Å)