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Between a rock and a hard place?

Nature Chemical Biology volume 2, pages 112–118 (2006)Cite this article

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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Figure 1: Examples of small-molecule inhibitors of PPI targets.
Figure 2: Balancing chemical and biological risk.
Figure 3: Why it can be difficult to identify small molecules that bind with high affinity to PPI targets.
Figure 4: Energetic hotspots and adaptivity.
Figure 5: Lead-optimization funnel.
Figure 6: Unusual inhibition mechanism of a small-molecule antagonist of the trimeric cytokine TNFα (ref. 19).
Figure 7

References

  1. Cochran, A. Chem. Biol. 7, R85–R94 (2000).

    Article  CAS  Google Scholar 

  2. Toogood, P.L. J. Med. Chem. 45, 1543–1558 (2002).

    Article  CAS  Google Scholar 

  3. Arkin, M.R. & Wells, J.A. Nat. Rev. Drug Discov. 3, 301–317 (2004).

    Article  CAS  Google Scholar 

  4. Fisher, P.M. Drug Design Rev. 2, 179–207 (2005).

    Article  Google Scholar 

  5. Hajduk, P.J. & Burns, D.J. Comb. Chem. High Throughput Screen. 5, 613–621 (2002).

    Article  CAS  Google Scholar 

  6. Puppo, F., Murdaca, G., Ghio, M. & Indiveri, F. Autoimmun. Rev. 4, 537–541 (2005).

    Article  CAS  Google Scholar 

  7. Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. Adv. Drug Deliv. Rev. 23, 3–25 (1997).

    Article  CAS  Google Scholar 

  8. Jencks, W.P. Adv. Enz. Rel. Areas Molec. Biol. 43, 219–410 (1975).

    CAS  Google Scholar 

  9. Clackson, T. & Wells, J.A. Science 267, 383–386 (1995).

    Article  CAS  Google Scholar 

  10. Arkin, M.R. et al. Proc. Natl. Acad. Sci. USA 100, 1603–1608 (2003).

    Article  CAS  Google Scholar 

  11. Teague, S.J. Nat. Rev. Drug Discov. 2, 527–541 (2003).

    Article  CAS  Google Scholar 

  12. Rees, D.C., Congreve, M., Murray, C.W. & Carr, R. Nat. Rev. Drug Discov. 3, 660–672 (2004).

    Article  CAS  Google Scholar 

  13. Erlanson, D.A., McDowell, R.S. & O'Brien, T. J. Med. Chem. 47, 3463–3482 (2004).

    Article  CAS  Google Scholar 

  14. Shuker, S.B., Hajduk, P.J., Meadows, R.P. & Fesik, S.W. Science 274, 1531–1534 (1996).

    Article  CAS  Google Scholar 

  15. Hajduk, P.J., Meadows, R.P. & Fesik, S.W. Science 278, 497–499 (1997).

    Article  CAS  Google Scholar 

  16. Erlanson, D.A. et al. Proc. Natl. Acad. Sci. USA 97, 9367–9372 (2000).

    Article  CAS  Google Scholar 

  17. Whitty, A. & Borysenko, C.W. Chem. Biol. 6, R107–R118 (1999).

    Article  CAS  Google Scholar 

  18. McGovern, S.L. & Shoichet, B.K. J. Med. Chem. 46, 1478–1483 (2003).

    Article  CAS  Google Scholar 

  19. He, M.M. et al. Science 310, 1022–1025 (2005).

    Article  CAS  Google Scholar 

  20. Pellecchia, M. et al. Expert Opin. Ther. Targets 8, 597–611 (2004).

    Article  CAS  Google Scholar 

  21. Oltersdorf, T. et al. Nature 435, 677–681 (2005).

    Article  CAS  Google Scholar 

  22. Braisted, A.C. et al. J. Am. Chem. Soc. 125, 3714–3715 (2003).

    Article  CAS  Google Scholar 

  23. Fellouse, F.A., Weismann, C. & Sidhu, S.S. Proc. Natl. Acad. Sci. USA 101, 12467–12472 (2004).

    Article  CAS  Google Scholar 

  24. Hajduk, P.J., Bures, M., Praestgaard, J. & Fesik, S.W. J. Med. Chem. 43, 3443–3447 (2000).

    Article  CAS  Google Scholar 

  25. Koehn, F.E. & Carter, G.T. Nat. Rev. Drug Discov. 4, 206–220 (2005).

    Article  CAS  Google Scholar 

  26. Veber, D.F. et al. J. Med. Chem. 45, 2615–2613 (2002).

    Article  CAS  Google Scholar 

  27. Schreiber, S.L. Science 287, 1964–1969 (2000).

    Article  CAS  Google Scholar 

  28. Reayi, A. & Arya, P. Curr. Opin. Chem. Biol. 9, 240–247 (2005).

    Article  CAS  Google Scholar 

  29. Vassilev, L.T. et al. Science 303, 844–848 (2004).

    Article  CAS  Google Scholar 

  30. Hajduk, P.J., Huth, J.R. & Tse, C. Drug Discov. Today 10, 1675–1682 (2005).

    Article  CAS  Google Scholar 

  31. Hajduk, P.J., Huth, J.R. & Fesik, S.W. J. Med. Chem. 48, 2518–2525 (2005).

    Article  CAS  Google Scholar 

  32. Tilley, J.W. et al. J. Am. Chem. Soc. 119, 7589–7590 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

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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  1. the Drug Discovery Department, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Adrian Whitty & Gnanasambandam Kumaravel

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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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