6K04

Crystal structure of BRD2(BD2)with ligand BY27 bound

Summary for 6K04

• Entry DOI: 10.2210/pdb6k04/pdb
• Descriptor: Bromodomain-containing protein 2, (6~{R})-~{N}-(4-chlorophenyl)-1-methyl-8-(1-methylpyrazol-4-yl)-5,6-dihydro-4~{H}-[1,2,4]triazolo[4,3-a][1]benzazepin-6-amine (3 entities in total)
• Functional Keywords: antitumor; bet proteins; bromodomain inhibitor; epigenetic readers, antitumor protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 13562.03

Authors

Lu, T.,Lu, W.,Chen, D.,Zhao, Y.,Luo, C. (deposition date: 2019-05-05, release date: 2019-09-18, Last modification date: 2023-11-22)

Primary citation

Chen, D.,Lu, T.,Yan, Z.,Lu, W.,Zhou, F.,Lyu, X.,Xu, B.,Jiang, H.,Chen, K.,Luo, C.,Zhao, Y.
Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Eur.J.Med.Chem., 182:111633-111633, 2019

PubMed Abstract: Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.

PubMed: 31461688
DOI: 10.1016/j.ejmech.2019.111633

Experimental method

X-RAY DIFFRACTION (1.251 Å)