1ysn
From Proteopedia
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'''Solution structure of the anti-apoptotic protein Bcl-xL complexed with an acyl-sulfonamide-based ligand''' | '''Solution structure of the anti-apoptotic protein Bcl-xL complexed with an acyl-sulfonamide-based ligand''' | ||
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[[Category: Wendt, M D.]] | [[Category: Wendt, M D.]] | ||
[[Category: Zhang, H.]] | [[Category: Zhang, H.]] | ||
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| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 16:44:05 2008'' | |
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Revision as of 13:44, 3 May 2008
Solution structure of the anti-apoptotic protein Bcl-xL complexed with an acyl-sulfonamide-based ligand
Overview
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.
About this Structure
1YSN is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
An inhibitor of Bcl-2 family proteins induces regression of solid tumours., Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Nature. 2005 Jun 2;435(7042):677-81. Epub 2005 May 15. PMID:15902208 Page seeded by OCA on Sat May 3 16:44:05 2008
Categories: Homo sapiens | Single protein | Armstrong, R C. | Augeri, D J. | Belli, B A. | Bruncko, M. | Connor, J M.O. | Deckwerth, T L. | Dinges, J. | Elmore, S W. | Fesik, S W. | Hajduk, P J. | Joseph, M K. | Kitada, S. | Korsmeyer, S J. | Kunzer, A R. | Letai, A. | Li, C. | Mitten, M J. | Nettesheim, D G. | Ng, S. | Nimmer, P M. | Oleksijew, A. | Oltersdorf, T. | Petros, A M. | Reed, J C. | Rosenberg, S H. | Shen, W. | Shoemaker, A R. | Tahir, S K. | Thompson, C B. | Tomaselli, K J. | Wang, B. | Wendt, M D. | Zhang, H. | Apoptosis | Complex
