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.
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We thank T. J. Kipps, L. Rassenti, J. Gribben and L. Vallat for CLL Research Consortium samples, E. Monosov for assistance with confocal imaging, C. Rudin and C. Hann for H345 xenograft studies, and S. Ackler for compound formulation.
S.W.E., A.R.S., D.J.A., M.B., J.D., P.J.H., M.K.J., A.R.K, M.J.M., D.G.N., S-C.H., P.M.N., J.M.O'C., A.O., A.M.P., W.S., S.K.T., B.W., M.D.W., H.Z., S.W.F. and S.H.R. are current or recent employees of Abbott Laboratories. T.O., K.J.T., R.C.A., B.A.B. and T.L. D. are current or recent employees of Idun Pharmaceuticals.
This figure summarizes the synthetic scheme for the chemical synthesis of ABT-737. (PDF 28 kb)
This figure contains NMR-derived structures that illustrate the differences between the binding pockets of Bcl-2 and Bcl-XL. (PPT 2187 kb)
This figure illustrates the effects of ABT-737 on cytochrome c release from mitochondria isolated from Bak-/-Bax-/- cells that had been stably transfected with either Bak, Bax, or a control plasmid. (PPT 943 kb)
This figure illustrates the enhanced survival effected by ABT-737 in the DoHH-2 systemic model of B-cell Lymphoma. (PPT 35 kb)
This file contains NMR and structural statistics for the protein complexes illustrated in Figure 1 and Supplementary Figure 2. (DOC 64 kb)
Legends for Supplementary Figures S1-S4. (DOC 56 kb)
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Oltersdorf, T., Elmore, S., Shoemaker, A. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005). https://doi.org/10.1038/nature03579
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