An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
Oltersdorf, Tilman 1*; Elmore, Steven W. 2*; Shoemaker, Alexander R. 2*; Armstrong, Robert C. 1; Augeri, David J. 2; Belli, Barbara A. 1; Bruncko, Milan 2; Deckwerth, Thomas L. 1; Dinges, Jurgen 2; Hajduk, Philip J. 2; Joseph, Mary K. 2; Kitada, Shinichi 3; Korsmeyer, Stanley J. 4,5; Kunzer, Aaron R. 2; Letai, Anthony 5; Li, Chi 6; Mitten, Michael J. 2; Nettesheim, David G. 2; Ng, ShiChung 2; Nimmer, Paul M. 2; O'Connor, Jacqueline M. 2; Oleksijew, Anatol 2; Petros, Andrew M. 2; Reed, John C. 3; Shen, Wang 2; Tahir, Stephen K. 2; Thompson, Craig B. 6; Tomaselli, Kevin J. 1; Wang, Baole 2; Wendt, Michael D. 2; Zhang, Haichao 2; Fesik, Stephen W. 2; Rosenberg, Saul H. 2
[Letter]
Nature.
435(7042):677-681, June 2, 2005.
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Proteins in the Bcl-2 family are central regulators of programmed cell death 1, and members that inhibit apoptosis, such as Bcl-XL and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy 2. Bcl-XL expression correlates with chemo-resistance of tumour cell lines 3, and reductions in Bcl-2 increase sensitivity to anticancer drugs 4 and enhance in vivo survival 5. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored 6-15, 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-XL and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds 7-15. 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.
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