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| [[Image:1ysg.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_1ysg| PDB=1ysg | SCENE= }} | | {{STRUCTURE_1ysg| PDB=1ysg | SCENE= }} |
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| '''Solution Structure of the Anti-apoptotic Protein Bcl-xL in Complex with "SAR by NMR" Ligands'''
| | ===Solution Structure of the Anti-apoptotic Protein Bcl-xL in Complex with "SAR by NMR" Ligands=== |
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| ==Overview==
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| Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.
| | The line below this paragraph, {{ABSTRACT_PUBMED_15902208}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15902208 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15902208}} |
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| ==About this Structure== | | ==About this Structure== |
| 1YSG is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YSG OCA]. | | 1YSG is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YSG OCA]. |
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| ==Reference== | | ==Reference== |
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| [[Category: Apoptosis]] | | [[Category: Apoptosis]] |
| [[Category: Complex]] | | [[Category: Complex]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 16:43:33 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 18:34:20 2008'' |
