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

Nature Chemical Biology volume 5, pages 154–156 (2009)Cite this article

Abstract

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.

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

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Acknowledgements

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.

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Author notes

  1. Benjamin Z Stanton and Lee F Peng: These authors contributed equally to this work.

Authors and Affiliations

  1. The Howard Hughes Medical Institute at the Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Benjamin Z Stanton, Lee F Peng, Nicole Maloof, Xiang Wang, Jay L Duffner, Kennedy M Taveras, Angela N Koehler & Stuart L Schreiber

  2. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, 02138, Massachusetts, USA

    Benjamin Z Stanton, Lee F Peng, Kazuo Nakai & Stuart L Schreiber

  3. Department of Medicine, Gastrointenstinal Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Lee F Peng

  4. Department of Chemical and Systems Biology, Stanford University School of Medicine, 269 Campus Drive, CCSR 3155, Stanford, 94305, California, USA

    Joel M Hyman & James K Chen

  5. Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, 02129, Massachusetts, USA

    Sam W Lee & Anna Mandinova

  6. Department of Stem Cell and Regenerative Biology, Harvard University, 42 Church Street, Cambridge, 02138, Massachusetts, USA

    Julia L Fox

Authors
  1. Benjamin Z Stanton
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  11. James K Chen
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Corresponding authors

Correspondence to Lee F Peng or Stuart L Schreiber.

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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.

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

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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). https://doi.org/10.1038/nchembio.142

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