6q3y: Difference between revisions
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==Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16i== | |||
<StructureSection load='6q3y' size='340' side='right' caption='[[6q3y]], [[Resolution|resolution]] 1.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6q3y]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q3Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q3Y FirstGlance]. <br> | |||
</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=HG5:(7~{R})-2-[[2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl]amino]-7-ethyl-5-methyl-8-(phenylmethyl)-7~{H}-pteridin-6-one'>HG5</scene></td></tr> | |||
<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=6q3y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q3y OCA], [http://pdbe.org/6q3y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q3y RCSB], [http://www.ebi.ac.uk/pdbsum/6q3y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q3y ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[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> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6q3y" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Arrowsmith, C H]] | |||
[[Category: Bountra, C]] | |||
[[Category: Edwards, A M]] | |||
[[Category: Heidenreich, D]] | |||
[[Category: Hoelder, S]] | |||
[[Category: Knapp, S]] | |||
[[Category: Structural genomic]] | |||
[[Category: Watts, E]] | |||
[[Category: Complex]] | |||
[[Category: Gene regulation]] | |||
[[Category: Inhibitor]] | |||
[[Category: Sgc]] | |||
