Developing small-molecule inhibitors against protein-protein interaction targets is among the most difficult challenges in contemporary drug discovery. Recent developments in our understanding of this problem, and in the knowledge and tools available to address it, give cause for renewed hope, but substantial challenges remain.
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References
Cochran, A. Chem. Biol. 7, R85–R94 (2000).
Toogood, P.L. J. Med. Chem. 45, 1543–1558 (2002).
Arkin, M.R. & Wells, J.A. Nat. Rev. Drug Discov. 3, 301–317 (2004).
Fisher, P.M. Drug Design Rev. 2, 179–207 (2005).
Hajduk, P.J. & Burns, D.J. Comb. Chem. High Throughput Screen. 5, 613–621 (2002).
Puppo, F., Murdaca, G., Ghio, M. & Indiveri, F. Autoimmun. Rev. 4, 537–541 (2005).
Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. Adv. Drug Deliv. Rev. 23, 3–25 (1997).
Jencks, W.P. Adv. Enz. Rel. Areas Molec. Biol. 43, 219–410 (1975).
Clackson, T. & Wells, J.A. Science 267, 383–386 (1995).
Arkin, M.R. et al. Proc. Natl. Acad. Sci. USA 100, 1603–1608 (2003).
Teague, S.J. Nat. Rev. Drug Discov. 2, 527–541 (2003).
Rees, D.C., Congreve, M., Murray, C.W. & Carr, R. Nat. Rev. Drug Discov. 3, 660–672 (2004).
Erlanson, D.A., McDowell, R.S. & O'Brien, T. J. Med. Chem. 47, 3463–3482 (2004).
Shuker, S.B., Hajduk, P.J., Meadows, R.P. & Fesik, S.W. Science 274, 1531–1534 (1996).
Hajduk, P.J., Meadows, R.P. & Fesik, S.W. Science 278, 497–499 (1997).
Erlanson, D.A. et al. Proc. Natl. Acad. Sci. USA 97, 9367–9372 (2000).
Whitty, A. & Borysenko, C.W. Chem. Biol. 6, R107–R118 (1999).
McGovern, S.L. & Shoichet, B.K. J. Med. Chem. 46, 1478–1483 (2003).
He, M.M. et al. Science 310, 1022–1025 (2005).
Pellecchia, M. et al. Expert Opin. Ther. Targets 8, 597–611 (2004).
Oltersdorf, T. et al. Nature 435, 677–681 (2005).
Braisted, A.C. et al. J. Am. Chem. Soc. 125, 3714–3715 (2003).
Fellouse, F.A., Weismann, C. & Sidhu, S.S. Proc. Natl. Acad. Sci. USA 101, 12467–12472 (2004).
Hajduk, P.J., Bures, M., Praestgaard, J. & Fesik, S.W. J. Med. Chem. 43, 3443–3447 (2000).
Koehn, F.E. & Carter, G.T. Nat. Rev. Drug Discov. 4, 206–220 (2005).
Veber, D.F. et al. J. Med. Chem. 45, 2615–2613 (2002).
Schreiber, S.L. Science 287, 1964–1969 (2000).
Reayi, A. & Arya, P. Curr. Opin. Chem. Biol. 9, 240–247 (2005).
Vassilev, L.T. et al. Science 303, 844–848 (2004).
Hajduk, P.J., Huth, J.R. & Tse, C. Drug Discov. Today 10, 1675–1682 (2005).
Hajduk, P.J., Huth, J.R. & Fesik, S.W. J. Med. Chem. 48, 2518–2525 (2005).
Tilley, J.W. et al. J. Am. Chem. Soc. 119, 7589–7590 (1997).
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We thank R. McDowell and M. He for providing Figures 4 and 6, respectively, and J. Huth for critically reading the manuscript.
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Whitty, A., Kumaravel, G. Between a rock and a hard place?. Nat Chem Biol 2, 112–118 (2006). https://doi.org/10.1038/nchembio0306-112
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DOI: https://doi.org/10.1038/nchembio0306-112
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