5z5t

The first bromodomain of BRD4 with compound BDF-2141

spinqualitylabelsall models 5z5t, resolution 1.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5z5t is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.991Å Ligands: 96R Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. Function BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMed Small molecular inhibitors targeting BRD4 family proteins are emerging as promising therapies in many types of human malignancies. However, whether BRD4, as well as other BET family members, may serve as therapeutic targets in renal cell carcinoma (RCC) remains unknown. In this study, we found that both BRD2 and BRD4 were over-expressed in RCC tissues, knock-down both of which achieved potent anti-proliferative effects in RCC cells. A novel category of BET inhibitors, originated from an approved drug Nitroxoline, were synthesized and evaluated with biochemical and cellular assays, as well as the method of crystallography. The complex crystal structures of several compounds in this category with the first bromodomain of BRD4 (BRD4-BD1) were solved, revealing the binding mechanism and facilitating further structural optimizations. Among them, compound BDF-1253 showed an approximately four-fold improvement in BRD4 inhibition compared with the prototype Nitroxoline and had good selectivity for BET proteins against other bromodomain proteins or epi-enzymes in biochemical assays. Compound BDF-1253 efficiently suppressed the expression of BET downstream genes, impaired RCC cells viability via inducing cell cycle arrest and apoptosis, and decreased tumor growth in RCC xenografts. In summary, these results suggest that inhibition of BET family members has great therapeutic potentials in the treatment of RCC, and the novel series of BET inhibitors reported here are promising to become RCC drug candidates. Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma.,Chen W, Zhang H, Chen Z, Jiang H, Liao L, Fan S, Xing J, Xie Y, Chen S, Ding H, Chen K, Jiang H, Luo C, Zheng M, Yao Z, Huang Y, Zhang Y Oncogenesis. 2018 Nov 2;7(11):83. doi: 10.1038/s41389-018-0093-z. PMID:30385738 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bromodomain-containing protein 3D structures Histone 3D structures

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