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

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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Correspondence to Lee F Peng or Stuart L Schreiber.

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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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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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