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

Proteins in the Bcl-2 family are central regulators of programmed cell death(1), 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(2). Bcl-X-L 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-X-L 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.