4HXL

Brd4 Bromodomain 1 complex with 3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE inhibitor

Summary for 4HXL

• Entry DOI: 10.2210/pdb4hxl/pdb
• Related: 4HXK 4HXM 4HXN 4HXO 4HXP 4HXR 4HXS
• Descriptor: Bromodomain-containing protein 4, 3-cyclohexyl-N-{3-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)-5-[(thiophen-2-ylsulfonyl)amino]phenyl}propanamide (3 entities in total)
• Functional Keywords: brd4, bromodomain, four alpha helices, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): O60885
• Total number of polymer chains: 1
• Total formula weight: 15374.84

Authors

Chen, T.T.,Cao, D.Y.,Chen, W.Y.,Xiong, B.,Shen, J.K.,Xu, Y.C. (deposition date: 2012-11-12, release date: 2013-04-03, Last modification date: 2024-02-28)

Primary citation

Zhao, L.,Cao, D.,Chen, T.,Wang, Y.,Miao, Z.,Xu, Y.,Chen, W.,Wang, X.,Li, Y.,Du, Z.,Xiong, B.,Li, J.,Xu, C.,Zhang, N.,He, J.,Shen, J.
Fragment-Based Drug Discovery of 2-Thiazolidinones as Inhibitors of the Histone Reader BRD4 Bromodomain.
J.Med.Chem., 56:3833-3851, 2013

PubMed Abstract: Recognizing acetyllysine of histone is a vital process of epigenetic regulation that is mediated by a protein module called bromodomain. To contribute novel scaffolds for developing into bromodomain inhibitors, we utilize a fragment-based drug discovery approach. By successively applying docking and X-ray crystallography, we were able to identify 9 fragment hits from diffracting more than 60 crystals. In the present work, we described four of them and carried out the integrated lead optimization for fragment 8, which bears a 2-thiazolidinone core. After several rounds of structure guided modifications, we assessed the druggability of 2-thiazolidinone by modulating in vitro pharmacokinetic studies and cellular activity assay. The results showed that two potent compounds of 2-thiazolidinones have good metabolic stability. Also, the cellular assay confirmed the activities of 2-thiazolidinones. Together, we hope the identified 2-thiazolidinone chemotype and other fragment hits described herein can stimulate researchers to develop more diversified bromodomain inhibitors.

PubMed: 23530754
DOI: 10.1021/jm301793a

Experimental method

X-RAY DIFFRACTION (1.52 Å)