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

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Abstract
Bcl-2 proteins are important regulators of programmed cell death (apoptosis) and are overexpressed in many cancers, contributing to tumour growth and resistance to treatment. Some of the latest techniques in drug design, including NMR-based screening, parallel synthesis, and structure-based design, have been used to develop a new small-molecule Bcl-2 inhibitor called ABT-737. It is three orders of magnitude more potent than any previous Bcl-2 inhibitor, and it looks as if this compound could be useful therapeutically. On its own, ABT-737 kills some cancer cell lines, including cells from lymphoma and small-cell lung carcinomas; in addition, it enhances the effects of chemotherapeutics and radiation on other cancer cell lines. Proteins in the Bcl-2 family are central regulators of programmed cell death1, 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 therapy2. Bcl-XL expression correlates with chemo-resistance of tumour cell lines3, and reductions in Bcl-2 increase sensitivity to anticancer drugs4 and enhance in vivo survival5. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored6,7,8,9,10,11,12,13,14,15, 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 compounds7,8,9,10,11,12,13,14,15. 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.