5YOV

Crystal structure of BRD4-BD1 bound with hjp126

Summary for 5YOV

• Entry DOI: 10.2210/pdb5yov/pdb
• Descriptor: Bromodomain-containing protein 4, (3~{R})-4-cyclopentyl-~{N}-(2,4-dimethylphenyl)-1,3-dimethyl-2-oxidanylidene-3~{H}-quinoxaline-6-carboxamide (3 entities in total)
• Functional Keywords: bromodomain, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15490.89

Authors

Xiong, B.,Hu, J.,Li, Y.,Cao, D. (deposition date: 2017-10-31, release date: 2018-11-07, Last modification date: 2024-03-27)

Primary citation

Hu, J.,Wang, Y.,Li, Y.,Cao, D.,Xu, L.,Song, S.,Damaneh, M.S.,Li, J.,Chen, Y.,Wang, X.,Chen, L.,Shen, J.,Miao, Z.,Xiong, B.
Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups.
Eur.J.Med.Chem., 150:156-175, 2018

PubMed Abstract: Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9, 28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 μM. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors.

PubMed: 29525435
DOI: 10.1016/j.ejmech.2018.02.070

Experimental method

X-RAY DIFFRACTION (1.451 Å)