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- Title
An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
- Authors
Oltersdorf, Tilman; Elmore, Steven W; Shoemaker, Alexander R; Armstrong, Robert C; Augeri, David J; Belli, Barbara A; Bruncko, Milan; Deckwerth, Thomas L; Dinges, Jurgen; Hajduk, Philip J; Joseph, Mary K; Kitada, Shinichi; Korsmeyer, Stanley J; Kunzer, Aaron R; Letai, Anthony; Li, Chi; Mitten, Michael J; Nettesheim, David G; Ng, ShiChung; Nimmer, Paul M; O'Connor, Jacqueline M; Oleksijew, Anatol; Petros, Andrew M; Reed, John C; Shen, Wang; Tahir, Stephen K; Thompson, Craig B; Tomaselli, Kevin J; Wang, Baole; Wendt, Michael D; Zhang, Haichao; Fesik, Stephen W; Rosenberg, Saul H
- Abstract
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.
- Publication
Nature, 2005, Vol 435, Issue 7042, p677
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature03579