1. Idun Pharmaceuticals, 9380 Judicial Drive, San Diego, California 92121, USA
2. Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA
3. The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
4. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
5. Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
6. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
7. *These authors contributed equally to this work

Correspondence to: Stephen W. Fesik²Saul H. Rosenberg² Correspondence and requests for materials should be addressed to S.H.R. (Email: saul.rosenberg@abbott.com) or S.W.F. (Email: stephen.fesik@abbott.com).

Proteins in the Bcl-2 family are central regulators of programmed cell death¹, 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 therapy². Bcl-X_L 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 explored^{6, 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-X_L and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds^{7, 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.

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