7axr: Difference between revisions
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==Crystal structure of BRD4(1) bound to the dual BET-HDAC inhibitor LSH24== | ==Crystal structure of BRD4(1) bound to the dual BET-HDAC inhibitor LSH24== | ||
<StructureSection load='7axr' size='340' side='right'caption='[[7axr]]' scene=''> | <StructureSection load='7axr' size='340' side='right'caption='[[7axr]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AXR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AXR FirstGlance]. <br> | <table><tr><td colspan='2'>[[7axr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AXR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AXR FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7axr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7axr OCA], [https://pdbe.org/7axr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7axr RCSB], [https://www.ebi.ac.uk/pdbsum/7axr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7axr ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S7T:4-acetyl-3-ethyl-N-(3-(3-(hydroxyamino)-3-oxopropyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide'>S7T</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7axr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7axr OCA], [https://pdbe.org/7axr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7axr RCSB], [https://www.ebi.ac.uk/pdbsum/7axr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7axr ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://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 == | |||
[[https://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 == | |||
Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibitors. The most promising new hybrids, 49 and 61, displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. 49 induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, 61, induced significantly more apoptosis than the related control compounds 62 (no BRD4(1) affinity) and 63 (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds. | |||
4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads.,Schaker-Hubner L, Warstat R, Ahlert H, Mishra P, Kraft FB, Schliehe-Diecks J, Scholer A, Borkhardt A, Breit B, Bhatia S, Hugle M, Gunther S, Hansen FK J Med Chem. 2021 Sep 28. doi: 10.1021/acs.jmedchem.1c01119. PMID:34582215<ref>PMID:34582215</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7axr" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Huegle M]] | [[Category: Huegle, M]] | ||
[[Category: Bd1]] | |||
[[Category: Bet]] | |||
[[Category: Beti]] | |||
[[Category: Brd4]] | |||
[[Category: Bromodomain]] | |||
[[Category: Dual inhibitor]] | |||
[[Category: First bromodomain]] | |||
[[Category: Hdac]] | |||
[[Category: Hdaci]] | |||
[[Category: Lsh24]] | |||
[[Category: Protein binding]] | |||
Revision as of 12:48, 13 October 2021
Crystal structure of BRD4(1) bound to the dual BET-HDAC inhibitor LSH24
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