Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A small molecule that binds Hedgehog and blocks its signaling in human cells


Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Characterization of SMM hit 1.
Figure 2: Robotnikinin.


  1. Ingham, P.W. & McMahon, A.P. Genes Dev. 15, 3059–3087 (2001).

    Article  CAS  Google Scholar 

  2. Rubin, L. & de Sauvage, F.J. Nat. Rev. Drug Discov. 5, 1026–1033 (2006).

    Article  CAS  Google Scholar 

  3. Nusslein-Volhard, C. & Wieschaus, E. Nature 287, 795–801 (1980).

    Article  CAS  Google Scholar 

  4. Chen, J.K., Taipale, J., Young, K.E., Maiti, T. & Beachy, P.A. Proc. Natl. Acad. Sci. USA 99, 14071–14076 (2002).

    Article  CAS  Google Scholar 

  5. Chen, J.K., Taipale, J., Cooper, M.K. & Beachy, P.A. Genes Dev. 16, 2743–2748 (2002).

    Article  CAS  Google Scholar 

  6. Williams, J.A. et al. Proc. Natl. Acad. Sci. USA 100, 4616–4621 (2003).

    Article  CAS  Google Scholar 

  7. Ding, S. & Schultz, P.G. Nat. Biotechnol. 22, 833–840 (2004).

    Article  CAS  Google Scholar 

  8. Wu, X. et al. Chem. Biol. 11, 1229–1238 (2004).

    Article  CAS  Google Scholar 

  9. Wang, B., Fallon, J.F. & Beachy, P.A. Cell 100, 423–434 (2000).

    Article  CAS  Google Scholar 

  10. Chiang, C. et al. Nature 383, 407–413 (1996).

    Article  CAS  Google Scholar 

  11. Thayer, S.P. et al. Nature 425, 851–856 (2003).

    Article  CAS  Google Scholar 

  12. Von Hoff, D.D. et al. in Proceedings of the 99th Annual Meeting of the American Association of Cancer Research, San Diego, April 12–16, 2008, abstract LB-138 (American Association of Cancer Research, Philadelphia, 2008).

    Google Scholar 

  13. Epstein, E.H. Nat. Rev. Cancer 8, 743–754 (2008).

    Article  CAS  Google Scholar 

  14. MacBeath, G., Koehler, A.N. & Schreiber, S.L. J. Am. Chem. Soc. 121, 7967–7968 (1999).

    Article  CAS  Google Scholar 

  15. Kuruvilla, F.G. et al. Nature 416, 653–657 (2002).

    Article  CAS  Google Scholar 

  16. Tan, D.S. Nat. Biotechnol. 20, 561–563 (2002).

    Article  CAS  Google Scholar 

  17. Burke, M.D., Berger, E.M. & Schreiber, S.L. Science 302, 613–618 (2003).

    Article  CAS  Google Scholar 

  18. Wong, J.C. et al. Chem. Biol. 11, 1279–1291 (2004).

    Article  CAS  Google Scholar 

  19. Bradner, J.E. et al. Chem. Biol. 13, 493–504 (2006).

    Article  CAS  Google Scholar 

  20. Taipale, J. et al. Nature 406, 1005–1009 (2000).

    Article  CAS  Google Scholar 

  21. Sinha, S. & Chen, J.K. Nat. Chem. Biol. 2, 29–30 (2006).

    Article  CAS  Google Scholar 

  22. Chen, J.K., Taipale, J., Cooper, M.K. & Beachy, P.A. Genes Dev. 16, 2743–2748 (2002).

    Article  CAS  Google Scholar 

  23. Spinella-Jaegle, S. et al. J. Cell Sci. 114, 2085–2094 (2001).

    CAS  PubMed  Google Scholar 

  24. Yao, S., Lum, L. & Beachy, P.A. Cell 125, 343–357 (2006).

    Article  CAS  Google Scholar 

  25. Tenzen, T. et al. Dev. Cell 10, 647–656 (2006).

    Article  CAS  Google Scholar 

Download references


We thank M.A. Foley for suggesting the use of robotnikinin in primary cell and tissue models in the Mandinova laboratory, A.M. Stern for his insightful guidance and critique and G. Copeland, O. McPherson, D. Young and T. Lewis for their helpful suggestions. This work was funded by the US National Institute of General Medical Sciences (GM-38627 awarded to S.L.S.), the National Pancreas Foundation, American Gastroenterological Association and American Liver Foundation (L.F.P.), and in part with funds from the US National Cancer Institute's Initiative for Chemical Genetics (contract no. N01-CO-12400). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US government. S.L.S. is a Howard Hughes Medical Institute Investigator.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Lee F Peng or Stuart L Schreiber.

Ethics declarations

Competing interests

S.L.S. is a shareholder of Infinity Pharmaceuticals, a company to which reference is made in the text. All other authors declare that they have no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 and Supplementary Methods (PDF 557 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stanton, B., Peng, L., Maloof, N. et al. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol 5, 154–156 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing