4HXR
Brd4 Bromodomain 1 complex with N-[3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)PHENYL]THIOPHENE-2-SULFONAMIDE inhibitor
Summary for 4HXR
| Entry DOI | 10.2210/pdb4hxr/pdb |
| Related | 4HXK 4HXL 4HXM 4HXN 4HXO 4HXP 4HXS |
| Descriptor | Bromodomain-containing protein 4, N-[3-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)phenyl]thiophene-2-sulfonamide (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 | 15221.61 |
| 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 Cited by 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: 23530754DOI: 10.1021/jm301793a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.53 Å) |
Structure validation
Download full validation report
