6ton
From Proteopedia
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==Crystal structure of human BCL6 BTB domain in complex with compound 25b== | ==Crystal structure of human BCL6 BTB domain in complex with compound 25b== | ||
| - | <StructureSection load='6ton' size='340' side='right'caption='[[6ton]]' scene=''> | + | <StructureSection load='6ton' size='340' side='right'caption='[[6ton]], [[Resolution|resolution]] 2.36Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TON OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TON FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ton]] is a 2 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=6TON OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TON FirstGlance]. <br> |
| - | </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=6ton FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ton OCA], [http://pdbe.org/6ton PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ton RCSB], [http://www.ebi.ac.uk/pdbsum/6ton PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ton ProSAT]</span></td></tr> | + | </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=NR5:5-[[5-chloranyl-2-(2,2,6,6-tetramethylmorpholin-4-yl)pyrimidin-4-yl]amino]-1-methyl-3-(3-methyl-3-oxidanyl-butyl)benzimidazol-2-one'>NR5</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL6, BCL5, LAZ3, ZBTB27, ZNF51 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6ton FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ton OCA], [http://pdbe.org/6ton PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ton RCSB], [http://www.ebi.ac.uk/pdbsum/6ton PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ton ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/BCL6_HUMAN BCL6_HUMAN]] Note=Chromosomal aberrations involving BCL6 may be a cause of B-cell non-Hodgkin lymphoma. Translocation t(3;14)(q27;q32); translocation t(3;22)(q27;q11) with immunoglobulin gene regions. Note=A chromosomal aberration involving BCL6 may be a cause of a form of B-cell leukemia. Translocation t(3;11)(q27;q23) with POU2AF1/OBF1. Note=A chromosomal aberration involving BCL6 may be a cause of lymphoma. Translocation t(3;4)(q27;p11) with ARHH/TTF. | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/BCL6_HUMAN BCL6_HUMAN]] Transcriptional repressor which is required for germinal center formation and antibody affinity maturation. Probably plays an important role in lymphomagenesis.<ref>PMID:9649500</ref> <ref>PMID:18280243</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing. | ||
| + | |||
| + | Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.,Bellenie BR, Cheung KJ, Varela A, Pierrat OA, Collie GW, Box GM, Bright MD, Gowan S, Hayes A, Rodrigues MJ, Shetty KN, Carter M, Davis OA, Henley AT, Innocenti P, Johnson LD, Liu M, de Klerk S, Le Bihan YV, Lloyd MG, McAndrew PC, Shehu E, Talbot R, Woodward HL, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Hoelder S J Med Chem. 2020 Apr 10. doi: 10.1021/acs.jmedchem.9b02076. PMID:32275432<ref>PMID:32275432</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6ton" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Bihan, Y V.Le]] |
| - | [[Category: Rodrigues | + | [[Category: Montfort, R L.M van]] |
| - | [[Category: | + | [[Category: Rodrigues, M J]] |
| + | [[Category: Cancer]] | ||
| + | [[Category: Degrader]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Lymphoma]] | ||
| + | [[Category: Transcription]] | ||
Revision as of 06:35, 6 May 2020
Crystal structure of human BCL6 BTB domain in complex with compound 25b
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