4qvx: Difference between revisions
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==Discovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in Vivo== | ==Discovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in Vivo== | ||
<StructureSection load='4qvx' size='340' side='right' caption='[[4qvx]], [[Resolution|resolution]] 2.10Å' scene=''> | <StructureSection load='4qvx' size='340' side='right' caption='[[4qvx]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3CQ:2-[8-(1,3-BENZOTHIAZOL-2-YLCARBAMOYL)-3,4-DIHYDROISOQUINOLIN-2(1H)-YL]-5-(3-{4-[3-(DIMETHYLAMINO)PROP-1-YN-1-YL]-2-FLUOROPHENOXY}PROPYL)-1,3-THIAZOLE-4-CARBOXYLIC+ACID'>3CQ</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3CQ:2-[8-(1,3-BENZOTHIAZOL-2-YLCARBAMOYL)-3,4-DIHYDROISOQUINOLIN-2(1H)-YL]-5-(3-{4-[3-(DIMETHYLAMINO)PROP-1-YN-1-YL]-2-FLUOROPHENOXY}PROPYL)-1,3-THIAZOLE-4-CARBOXYLIC+ACID'>3CQ</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4tuh|4tuh]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4tuh|4tuh]]</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=4qvx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qvx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qvx RCSB], [http://www.ebi.ac.uk/pdbsum/4qvx PDBsum]</span></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=4qvx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qvx OCA], [http://pdbe.org/4qvx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qvx RCSB], [http://www.ebi.ac.uk/pdbsum/4qvx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qvx ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4qvx" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 17:23, 27 April 2017
Discovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in VivoDiscovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in Vivo
Structural highlights
Function[B2CL1_HUMAN] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.[1] [2] Isoform Bcl-X(S) promotes apoptosis.[3] [4] Publication Abstract from PubMedA-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization. Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.,Tao ZF, Hasvold L, Wang L, Wang X, Petros AM, Park CH, Boghaert ER, Catron ND, Chen J, Colman PM, Czabotar PE, Deshayes K, Fairbrother WJ, Flygare JA, Hymowitz SG, Jin S, Judge RA, Koehler MF, Kovar PJ, Lessene G, Mitten MJ, Ndubaku CO, Nimmer P, Purkey HE, Oleksijew A, Phillips DC, Sleebs BE, Smith BJ, Smith ML, Tahir SK, Watson KG, Xiao Y, Xue J, Zhang H, Zobel K, Rosenberg SH, Tse C, Leverson JD, Elmore SW, Souers AJ ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93. doi: 10.1021/ml5001867. eCollection, 2014 Oct 9. PMID:25313317[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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