5khm
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | The | + | ==The first BET bromodomain of BRD4 bound to compound 13 in a bivalent manner== |
| + | <StructureSection load='5khm' size='340' side='right' caption='[[5khm]], [[Resolution|resolution]] 1.48Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5khm]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KHM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KHM FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XNH:(3~{R})-4-[2-[4-[1-(3-METHOXY-[1,2,4]TRIAZOLO[4,3-B]PYRIDAZIN-6-YL)PIPERIDIN-4-YL]PHENOXY]ETHYL]-1,3-DIMETHYL-PIPERAZIN-2-ONE'>XNH</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=5khm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5khm OCA], [http://pdbe.org/5khm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5khm RCSB], [http://www.ebi.ac.uk/pdbsum/5khm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5khm 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 == | ||
| + | Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency. | ||
| - | + | Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phen oxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153).,Bradbury RH, Callis R, Carr GR, Chen H, Clark E, Feron L, Glossop S, Graham MA, Hattersley M, Jones C, Lamont SG, Ouvry G, Patel A, Patel J, Rabow AA, Roberts CA, Stokes S, Stratton N, Walker GE, Ward L, Whalley D, Whittaker D, Wrigley G, Waring MJ J Med Chem. 2016 Sep 8;59(17):7801-17. doi: 10.1021/acs.jmedchem.6b00070. Epub, 2016 Aug 24. PMID:27528113<ref>PMID:27528113</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 5khm" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Patel, J]] | [[Category: Patel, J]] | ||
| + | [[Category: Bromodomain]] | ||
| + | [[Category: Transcription factor]] | ||
Revision as of 13:55, 21 September 2016
The first BET bromodomain of BRD4 bound to compound 13 in a bivalent manner
| |||||||||||
