6p05

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==Bromodomain-containing protein 4 (BRD4) bromodomain 1 (BD1) complexed with compound 27==
==Bromodomain-containing protein 4 (BRD4) bromodomain 1 (BD1) complexed with compound 27==
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<StructureSection load='6p05' size='340' side='right'caption='[[6p05]]' scene=''>
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<StructureSection load='6p05' size='340' side='right'caption='[[6p05]], [[Resolution|resolution]] 1.54&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P05 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6P05 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6p05]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P05 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6P05 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6p05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p05 OCA], [http://pdbe.org/6p05 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p05 RCSB], [http://www.ebi.ac.uk/pdbsum/6p05 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p05 ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=YF2:N-{1-[1,1-di(pyridin-2-yl)ethyl]-6-(1-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indol-4-yl}ethanesulfonamide'>YF2</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6p05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p05 OCA], [http://pdbe.org/6p05 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p05 RCSB], [http://www.ebi.ac.uk/pdbsum/6p05 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p05 ProSAT]</span></td></tr>
</table>
</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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Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of 27 with BRD4. Optimization of BETi using growth inhibition in fulvestrant-resistant (MCF-7:CFR) cells was confirmed in endocrine-resistant, palbociclib-resistant, and ESR1 mutant cell lines. 27 was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated 27 from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of 27 in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated.
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Novel Pyrrolopyridone Bromodomain and Extra-Terminal Motif (BET) Inhibitors Effective in Endocrine-Resistant ER+ Breast Cancer with Acquired Resistance to Fulvestrant and Palbociclib.,Li Y, Zhao J, Gutgesell LM, Shen Z, Ratia K, Dye K, Dubrovskyi O, Zhao H, Huang F, Tonetti DA, Thatcher GRJ, Xiong R J Med Chem. 2020 Jun 15. doi: 10.1021/acs.jmedchem.0c00456. PMID:32453591<ref>PMID:32453591</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6p05" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Dubrovyskyii O]]
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[[Category: Dubrovyskyii, O]]
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[[Category: Dye K]]
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[[Category: Dye, K]]
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[[Category: Gutgesell LM]]
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[[Category: Gutgesell, L M]]
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[[Category: Huang F]]
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[[Category: Huang, F]]
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[[Category: Li Y]]
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[[Category: Li, Y]]
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[[Category: Ratia KM]]
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[[Category: Ratia, K M]]
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[[Category: Shen Z]]
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[[Category: Shen, Z]]
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[[Category: Thatcher GR]]
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[[Category: Thatcher, G R]]
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[[Category: Tonetti DA]]
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[[Category: Tonetti, D A]]
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[[Category: Xiong R]]
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[[Category: Xiong, R]]
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[[Category: Zhao H]]
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[[Category: Zhao, H]]
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[[Category: Zhao J]]
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[[Category: Zhao, J]]
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[[Category: Brd4]]
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[[Category: Bromodomain]]
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[[Category: Inhibitor]]
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[[Category: Transcription]]

Revision as of 10:35, 17 June 2020

Bromodomain-containing protein 4 (BRD4) bromodomain 1 (BD1) complexed with compound 27

PDB ID 6p05

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