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. 2005 Jun 2;435(7042):677-81.
doi: 10.1038/nature03579. Epub 2005 May 15.

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Tilman Oltersdorf  1 , Steven W Elmore, Alexander R Shoemaker, Robert C Armstrong, David J Augeri, Barbara A Belli, Milan Bruncko, Thomas L Deckwerth, Jurgen Dinges, Philip J Hajduk, Mary K Joseph, Shinichi Kitada, Stanley J Korsmeyer, Aaron R Kunzer, Anthony Letai, Chi Li, Michael J Mitten, David G Nettesheim, ShiChung Ng, Paul M Nimmer, Jacqueline M O'Connor, Anatol Oleksijew, Andrew M Petros, John C Reed, Wang Shen, Stephen K Tahir, Craig B Thompson, Kevin J Tomaselli, Baole Wang, Michael D Wendt, Haichao Zhang, Stephen W Fesik, Saul H Rosenberg
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Free article

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Tilman Oltersdorf et al. Nature. .
Free article

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.

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