5kdh

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH A DIHYDROPYRIDOPYRIMIDINE SCAFFOLD INHIBITOR

spinqualitylabelsall models 5kdh, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5kdh 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 1.5Å Ligands: 6RX, EDO, SO4 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 Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development. BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.,Ayoub AM, Hawk LML, Herzig RJ, Jiang J, Wisniewski AJ, Gee CT, Zhao P, Zhu JY, Berndt N, Offei-Addo NK, Scott TG, Qi J, Bradner JE, Ward TR, Schonbrunn E, Georg GI, Pomerantz WCK J Med Chem. 2017 Jun 22;60(12):4805-4817. doi: 10.1021/acs.jmedchem.6b01336. Epub, 2017 Jun 7. PMID:28535045 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bromodomain-containing protein 3D structures

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