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Know your target, know your molecule

Nature Chemical Biology volume 11, pages 368–372 (2015)Cite this article

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The pharmaceutical industry continues to experience significant attrition of drug candidates during phase 2 proof-of-concept clinical studies. We describe some questions about the characteristics of protein targets and small-molecule drugs that may be important to consider in drug-discovery projects and could improve prospects for future clinical success.

The issue of pharmaceutical R&D attrition has attracted significant interest in recent years. We have argued that the biggest opportunity to enhance overall R&D productivity is to focus on drug candidate survival through phase 2 and the selection of targets for which there is the highest confidence of relevance to human disease1,2. We have also highlighted the role that chemical biology can play in preclinical target validation through generation of high-quality chemical probes3 and have described the following four 'pillars' as a framework for target validation using such probes:

  1. 1

    exposure at site of action;

  2. 2

    demonstration of target occupancy;

  3. 3

    proof of mechanistic pharmacology and

  4. 4

    the use of disease-relevant phenotypic assays2,3.

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Figure 1: Graphical representation of mRNA expression levels of PDE4B isoforms in human tissues.
Figure 2: Emergence of ABPP technology.

References

  1. Bunnage, M.E. Nat. Chem. Biol. 7, 335–339 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Edwards, A.M. et al. Nat. Rev. Drug Discov. 14, 149–150 (2015).

    Article  PubMed  Google Scholar 

  3. Bunnage, M.E., Chekler, E.L.P. & Jones, L.H. Nat. Chem. Biol. 9, 195–199 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Morgan, P. et al. Drug Discov. Today 17, 419–424 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Huber, K.V.M. et al. Nature 508, 222–227 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weygant, N. et al. Mol. Cancer 13, 103 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lopez, M.S. et al. J. Am. Chem. Soc. 135, 18153–18159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

  9. Fox, D. III, Burgin, A.B. & Gurney, M.E. Cell. Signal. 26, 657–663 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Thorarensen, A. et al. ACS Chem. Biol. 9, 1552–1558 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Tate, E.W., Kalesh, K.A., Lanyon-Hogg, T., Storck, E.M. & Thinon, E. Curr. Opin. Chem. Biol. 24, 48–57 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Paulsen, C.E. & Carroll, K.S. Chem. Rev. 113, 4633–4679 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Honigberg, L.A. et al. Proc. Natl. Acad. Sci. USA 107, 13075–13080 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Padrón, D. et al. Cancer Res. 67, 7695–7702 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Polier, S. et al. Nat. Chem. Biol. 9, 307–312 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Neklesa, T.K. & Crews, C.M. Nature 487, 308–309 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Baell, J. & Walters, M.A. Nature 513, 481–483 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Patricelli, M.P. et al. Biochemistry 46, 350–358 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Lanning, B.R. et al. Nat. Chem. Biol. 10, 760–767 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bantscheff, M. et al. Nat. Biotechnol. 29, 255–265 (2011).

    CAS  PubMed  Google Scholar 

  21. Savitski, M.M. et al. Science 346, 1255784 (3 October 2014).

    Article  PubMed  Google Scholar 

  22. Ito, T. et al. Science 327, 1345–1350 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Winter, G.E. et al. Nat. Chem. Biol. 10, 768–773 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schwartz, P.A. et al. Proc. Natl. Acad. Sci. USA 111, 173–178 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Hatzivassiliou, G. et al. Nature 464, 431–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Ahn, K. et al. J. Pharmacol. Exp. Ther. 338, 114–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hett, E.C. et al. ACS Chem. Biol. 10, 1094–1098 (2015).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank many colleagues at Pfizer for their input on this topic, including T. Rolph and members of the 'chemical biology network group'. We also thank S. Hualin Xi for the graph shown in Figure 1, R. Stanton for his help in establishing the Wikipedia entry, and P. Workman (Institute of Cancer Research, UK) and A. Edwards (University of Toronto) for their helpful feedback.

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Authors and Affiliations

  1. Mark E. Bunnage, Lyn H. Jones and Erik C. Hett are in Worldwide Medicinal Chemistry at Pfizer, Cambridge, Massachusetts, USA.,

    Mark E Bunnage, Lyn H Jones & Erik C Hett

  2. Adam M. Gilbert is in Worldwide Medicinal Chemistry at Pfizer, Groton, Connecticut, USA.,

    Adam M Gilbert

Authors
  1. Mark E Bunnage
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Correspondence to Mark E Bunnage.

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All authors are employees and shareholders of Pfizer.

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Bunnage, M., Gilbert, A., Jones, L. et al. Know your target, know your molecule. Nat Chem Biol 11, 368–372 (2015). https://doi.org/10.1038/nchembio.1813

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