4uyh: Difference between revisions
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''' | ==N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-((2R,4S)-2-methyl-4-(phenylamino)-6-(4-(piperidin-1-ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone== | ||
<StructureSection load='4uyh' size='340' side='right' caption='[[4uyh]], [[Resolution|resolution]] 1.73Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4uyh]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UYH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UYH FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9S3:1-[(2S,4R)-2-METHYL-4-(PHENYLAMINO)-6-[4-(PIPERIDIN-1-YLMETHYL)PHENYL]-3,4-DIHYDROQUINOLIN-1(2H)-YL]ETHANONE'>9S3</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4uyd|4uyd]], [[4uye|4uye]], [[4uyf|4uyf]], [[4uyg|4uyg]]</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=4uyh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uyh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4uyh RCSB], [http://www.ebi.ac.uk/pdbsum/4uyh PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors. | |||
The | The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor.,Gosmini R, Nguyen VL, Toum J, Simon C, Brusq JM, Krysa G, Mirguet O, Riou-Eymard AM, Boursier EV, Trottet L, Bamborough P, Clark H, Chung CW, Cutler L, Demont EH, Kaur R, Lewis AJ, Schilling MB, Soden PE, Taylor S, Walker AL, Walker MD, Prinjha RK, Nicodeme E J Med Chem. 2014 Sep 24. PMID:25249180<ref>PMID:25249180</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bamborough, P.]] | |||
[[Category: Chung, C.]] | |||
[[Category: Gosmini, R.]] | |||
[[Category: Bet]] | |||
[[Category: Brd2]] | |||
[[Category: Bromodomain]] | |||
[[Category: Epigenetic reader]] | |||
[[Category: Histone]] | |||
[[Category: Transcription]] | |||
Revision as of 10:38, 8 October 2014
N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-((2R,4S)-2-methyl-4-(phenylamino)-6-(4-(piperidin-1-ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanoneN-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1-((2R,4S)-2-methyl-4-(phenylamino)-6-(4-(piperidin-1-ylmethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)ethanone
Structural highlights
Publication Abstract from PubMedThrough their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors. The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor.,Gosmini R, Nguyen VL, Toum J, Simon C, Brusq JM, Krysa G, Mirguet O, Riou-Eymard AM, Boursier EV, Trottet L, Bamborough P, Clark H, Chung CW, Cutler L, Demont EH, Kaur R, Lewis AJ, Schilling MB, Soden PE, Taylor S, Walker AL, Walker MD, Prinjha RK, Nicodeme E J Med Chem. 2014 Sep 24. PMID:25249180[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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