5y8c: Difference between revisions
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==Crystal Structure Analysis of the BRD4== | ==Crystal Structure Analysis of the BRD4== | ||
<StructureSection load='5y8c' size='340' side='right' caption='[[5y8c]], [[Resolution|resolution]] 1.42Å' scene=''> | <StructureSection load='5y8c' size='340' side='right'caption='[[5y8c]], [[Resolution|resolution]] 1.42Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5y8c]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y8C OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5y8c]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y8C OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5Y8C FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8P9:5-chloranyl-2-methoxy-N-(6-methoxy-3-methyl-1,2-benzoxazol-5-yl)benzenesulfonamide'>8P9</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8P9:5-chloranyl-2-methoxy-N-(6-methoxy-3-methyl-1,2-benzoxazol-5-yl)benzenesulfonamide'>8P9</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5y8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y8c OCA], [http://pdbe.org/5y8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y8c RCSB], [http://www.ebi.ac.uk/pdbsum/5y8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y8c ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5y8c" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5y8c" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Song, M]] | [[Category: Song, M]] | ||
[[Category: Wang, C]] | [[Category: Wang, C]] | ||
Revision as of 12:13, 21 October 2020
Crystal Structure Analysis of the BRD4Crystal Structure Analysis of the BRD4
Structural highlights
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.[1] [2] Function[BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedThe bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[ d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with Kd values of 82 and 81 nM, respectively. They also exhibited high selectivity over other non-BET subfamily members. The compounds potently inhibited cell growth, colony formation, and the expression of AR, AR regulated genes, and MYC in prostate cancer cell lines. Compounds 6i and 7m also demonstrated therapeutic effects in a C4-2B CRPC xenograft tumor model in mice. These potent and selective BET inhibitors represent a new class of compounds for the development of potential therapeutics against CRPC. Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC).,Zhang M, Zhang Y, Song M, Xue X, Wang J, Wang C, Zhang C, Li C, Xiang Q, Zou L, Wu X, Wu C, Dong B, Xue W, Zhou Y, Chen H, Wu D, Ding K, Xu Y J Med Chem. 2018 Apr 12;61(7):3037-3058. doi: 10.1021/acs.jmedchem.8b00103. Epub , 2018 Apr 3. PMID:29566488[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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