7EVJ

Crystal structure of CBP bromodomain liganded with 9c

Summary for 7EVJ

• Entry DOI: 10.2210/pdb7evj/pdb
• Descriptor: 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)
• Functional Keywords: histone acetyltransferase, cbp, bromodomain, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16597.89

Authors

Xiang, Q.,Wang, C.,Wu, T.,Zhang, Y.,Zhang, C.,Luo, G.,Wu, X.,Shen, H.,Xu, Y. (deposition date: 2021-05-21, release date: 2022-02-16, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.57 Å)