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6q3z

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'''Unreleased structure'''
 
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The entry 6q3z is ON HOLD
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==Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16k==
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<StructureSection load='6q3z' size='340' side='right' caption='[[6q3z]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6q3z]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q3Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q3Z FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HG8:(7~{R})-2-[[2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl]amino]-7-ethyl-5-methyl-8-[(4-methylthiophen-2-yl)methyl]-7~{H}-pteridin-6-one'>HG8</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6q3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q3z OCA], [http://pdbe.org/6q3z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q3z RCSB], [http://www.ebi.ac.uk/pdbsum/6q3z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q3z ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN 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.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-me thylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.
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Authors: Heidenreich, D., Watts, E., Arrowsmith, C.H., Bountra, C., Edwards, A.M., Knapp, S., Hoelder, S., Structural Genomics Consortium (SGC)
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Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.,Watts E, Heidenreich D, Tucker E, Raab M, Strebhardt K, Chesler L, Knapp S, Bellenie B, Hoelder S J Med Chem. 2019 Feb 21. doi: 10.1021/acs.jmedchem.8b01947. PMID:30789735<ref>PMID:30789735</ref>
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Description: Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16k
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6q3z" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Arrowsmith, C H]]
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[[Category: Bountra, C]]
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[[Category: Edwards, A M]]
[[Category: Heidenreich, D]]
[[Category: Heidenreich, D]]
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[[Category: Hoelder, S]]
[[Category: Knapp, S]]
[[Category: Knapp, S]]
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[[Category: Structural genomic]]
[[Category: Watts, E]]
[[Category: Watts, E]]
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[[Category: Edwards, A.M]]
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[[Category: Complex]]
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[[Category: Arrowsmith, C.H]]
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[[Category: Gene regulation]]
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[[Category: Structural Genomics Consortium (Sgc)]]
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[[Category: Inhibitor]]
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[[Category: Hoelder, S]]
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[[Category: Sgc]]
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[[Category: Bountra, C]]
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Revision as of 07:37, 6 March 2019

Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16k

6q3z, resolution 2.00Å

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