View source for 6saj


==Crystal Structure of BRD4(1) bound to inhibitor BUX6 (12)==
<StructureSection load='6saj' size='340' side='right'caption='[[6saj]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6saj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SAJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=L2Z:~{N}-[2-methoxy-5-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)phenyl]-3-methyl-4-oxidanylidene-5,6,7,8-tetrahydro-2~{H}-cyclohepta[c]pyrrole-1-carboxamide'>L2Z</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=6saj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6saj OCA], [https://pdbe.org/6saj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6saj RCSB], [https://www.ebi.ac.uk/pdbsum/6saj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6saj ProSAT]</span></td></tr>
</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 ==
Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI50 determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.

4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines.,Hugle M, Regenass P, Warstat R, Hau M, Schmidtkunz K, Lucas X, Wohlwend D, Einsle O, Jung M, Breit B, Gunther S J Med Chem. 2020 Dec 4. doi: 10.1021/acs.jmedchem.0c00478. PMID:33275431<ref>PMID:33275431</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6saj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Huegle M]]