7KPY

Crystal structure of CBP bromodomain liganded with UMB298 (compound 23)

7KPY の概要

• エントリーDOI: 10.2210/pdb7kpy/pdb
• 分子名称: Histone acetyltransferase, 1,2-ETHANEDIOL, 2-[2-(3-chloranyl-4-methoxy-phenyl)ethyl]-~{N}-cyclohexyl-7-(3,5-dimethyl-1,2-oxazol-4-yl)imidazo[1,2-a]pyridin-3-amine, ... (4 entities in total)
• 機能のキーワード: epigenetics, inhibitor, drug development, multi domain proteins, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28840.00

構造登録者

Schonbrunn, E.,Bikowitz, M. (登録日: 2020-11-12, 公開日: 2021-05-19, 最終更新日: 2023-10-18)

主引用文献

Muthengi, A.,Wimalasena, V.K.,Yosief, H.O.,Bikowitz, M.J.,Sigua, L.H.,Wang, T.,Li, D.,Gaieb, Z.,Dhawan, G.,Liu, S.,Erickson, J.,Amaro, R.E.,Schonbrunn, E.,Qi, J.,Zhang, W.
Development of Dimethylisoxazole-Attached Imidazo[1,2- a ]pyridines as Potent and Selective CBP/P300 Inhibitors.
J.Med.Chem., 64:5787-5801, 2021

PubMed Abstract: The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound , CBP IC 72 nM and bromodomain 4, BRD4 IC 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains.

PubMed: 33872011
DOI: 10.1021/acs.jmedchem.0c02232

実験手法

X-RAY DIFFRACTION (1.7 Å)