6X7C
BRD4 Bromodomain 1 in complex with multi-action inhibitor SRX3212
Summary for 6X7C
| Entry DOI | 10.2210/pdb6x7c/pdb |
| Descriptor | Bromodomain-containing protein 4, 7-[5-(morpholin-4-yl)-7-oxo-7H-thieno[3,2-b]pyran-3-yl]-N-[(pyridin-3-yl)methyl]-2,3-dihydro-1,4-benzodioxine-5-carboxamide (3 entities in total) |
| Functional Keywords | brd4, pi3k, cdk4/6, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 16359.79 |
| Authors | Vann, K.R.,Kutateladze, T.G. (deposition date: 2020-05-29, release date: 2020-08-05, Last modification date: 2023-10-18) |
| Primary citation | Vann, K.R.,Pal, D.,Morales, G.A.,Burgoyne, A.M.,Durden, D.L.,Kutateladze, T.G. Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets. Sci Rep, 10:12027-12027, 2020 Cited by PubMed Abstract: Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes. PubMed: 32694708DOI: 10.1038/s41598-020-68964-6 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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