4QR3

Brd4 Bromodomain 1 complex with its novel inhibitors

Summary for 4QR3

• Entry DOI: 10.2210/pdb4qr3/pdb
• Related: 4QR4 4QR5
• Descriptor: Bromodomain-containing protein 4, N-cyclopentyl-3-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)benzenesulfonamide (3 entities in total)
• Functional Keywords: brd4, bromodomain, four alpha helices, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15165.57

Authors

Xiong, B.,Cao, D.Y.,Chen, T.T.,Xu, Y.C. (deposition date: 2014-06-30, release date: 2015-07-01, Last modification date: 2024-03-20)

Primary citation

Zhao, L.,Wang, Y.,Cao, D.Y.,Chen, T.T.,Wang, Q.,Li, Y.,Xu, Y.C.,Zhang, N.,Wang, X.,Chen, D.,Chen, L.,Chen, Y.L.,Xia, G.,Shi, Z.,Liu, Y.C.,Lin, Y.,Miao, Z.,Shen, J.,Xiong, B.
Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization
J.Med.Chem., 58:1281-1297, 2015

PubMed Abstract: The signal transduction of acetylated histone can be processed through a recognition module, bromodomain. Several inhibitors targeting BRD4, one of the bromodomain members, are in clinical trials as anticancer drugs. Hereby, we report our efforts on discovery and optimization of a new series of 2-thiazolidinones as BRD4 inhibitors along our previous study. In this work, guided by crystal structure analysis, we reversed the sulfonamide group and identified a new binding mode. A structure-activity relationship study on this new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 μM in FP binding assay and GI50 of 0.1-0.3 μM in cell based assays. To complete the lead-like assessment of this series, we further checked its effects on BRD4 downstream protein c-Myc, investigated its selectivity among five different bromodomain proteins, as well as the metabolic stability test, and reinforced the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel anticancer drug development.

PubMed: 25559428
DOI: 10.1021/jm501504k

Experimental method

X-RAY DIFFRACTION (1.374 Å)