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| | <StructureSection load='6tpz' size='340' side='right'caption='[[6tpz]], [[Resolution|resolution]] 1.30Å' scene=''> | | <StructureSection load='6tpz' size='340' side='right'caption='[[6tpz]], [[Resolution|resolution]] 1.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6tpz]] 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=6TPZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TPZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6tpz]] 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=6TPZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TPZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NV2:5-[1-(1,3-dimethoxypropan-2-yl)-5-morpholin-4-yl-benzimidazol-2-yl]-1,3-dimethyl-pyridin-2-one'>NV2</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.299Å</td></tr> |
| - | <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>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NV2:5-[1-(1,3-dimethoxypropan-2-yl)-5-morpholin-4-yl-benzimidazol-2-yl]-1,3-dimethyl-pyridin-2-one'>NV2</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=6tpz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tpz OCA], [http://pdbe.org/6tpz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tpz RCSB], [http://www.ebi.ac.uk/pdbsum/6tpz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tpz ProSAT]</span></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=6tpz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tpz OCA], [https://pdbe.org/6tpz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tpz RCSB], [https://www.ebi.ac.uk/pdbsum/6tpz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tpz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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> | + | [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 == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). | + | [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 ==
| + | |
| - | The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
| + | |
| | | | |
| - | Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening.,Wellaway CR, Amans D, Bamborough P, Barnett H, Bit RA, Brown JA, Carlson NR, Chung CW, Cooper AWJ, Craggs PD, Davis RP, Dean TW, Evans JP, Gordon L, Harada IL, Hirst DJ, Humphreys PG, Jones KL, Lewis AJ, Lindon MJ, Lugo D, Mahmood M, McCleary S, Medeiros P, Mitchell DJ, O'Sullivan M, Le Gall A, Patel VK, Patten C, Poole DL, Shah RR, Smith JE, Stafford KAJ, Thomas PJ, Vimal M, Wall ID, Watson RJ, Wellaway N, Yao G, Prinjha RK J Med Chem. 2020 Jan 23;63(2):714-746. doi: 10.1021/acs.jmedchem.9b01670. Epub, 2020 Jan 6. PMID:31904959<ref>PMID:31904959</ref>
| + | ==See Also== |
| - | | + | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6tpz" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chung, C]] | + | [[Category: Chung C]] |
| - | [[Category: Antagonist]]
| + | |
| - | [[Category: Brd4]]
| + | |
| - | [[Category: Bromodomain]]
| + | |
| - | [[Category: Bromodomain containing protein 4]]
| + | |
| - | [[Category: Epigenetic reader]]
| + | |
| - | [[Category: Histone]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Transcription]]
| + | |
