4qvx

From Proteopedia

(Difference between revisions)

Revision as of 14:23, 27 April 2017

Discovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in Vivo

Structural highlights

4qvx is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4tuh
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

A-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

↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
↑ 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. Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity. ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93. doi: 10.1021/ml5001867. eCollection, 2014 Oct 9. PMID:25313317 doi:http://dx.doi.org/10.1021/ml5001867

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4qvx"

Categories: Park, C H | Alpha helice | Anti-apoptotic | Apoptosis-inhibitor complex | Pro-apoptotic

@@ Line 1: / Line 1: @@
 ==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]] 2.10&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </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='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>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4qvx" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4qvx

From Proteopedia

Revision as of 14:23, 27 April 2017

Discovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in Vivo

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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