Brief Communication | Published:

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

Nature Chemical Biology volume 5, pages 154156 (2009) | Download Citation

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.

  • Compound

    2-((3S,6S,12S,E)-12-Amino-3-methyl-5,13-dioxo-1-oxa-4-azacyclotridec-8-en-6-yl)-N-benzyl-N-(2-hydroxyethyl)acetamide

  • Compound

    Robotnikinin

  • Compound

    Cyclopamine

  • Compound

    (E)-4-Benzyl-N-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methylene)piperazin-1-amine

  • Compound

    N-((3S,5S)-1-(Benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide

  • Compound

    Purmorphamine

  • Compound

    3-Chloro-N-((4'-cyano-6-methoxybiphenyl-3-yl)methyl)-N-((1r,4r)-4-(methylamino)cyclohexyl)benzo[b]thiophene-2-carboxamide

  • Compound

    2,2'-(2-(Pyridin-4-yl)-dihydropyrimidine-1,3(2H,4H)-diyl)bis(methylene)bis(N,N-dimethylbenzenamine)

  • Compound

    4,4',4'',4'''-(Thiophene-2,3,4,5-tetrayl)tetrapyridine

  • Compound

    (R)-4-Benzyl-3-pent-4-enoyloxazolidin-2-one

  • Compound

    (S)-tert-Butyl 3-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)hex-5-enoate

  • Compound

    (S)-3-((R)-4-Benzyl-2-oxooxazolidine-3-carbonyl)hex-5-enoic acid

  • Compound

    (S)-3-((R)-4-Benzyl-2-oxooxazolidine-3-carbonyl)-N-(4-chlorobenzyl)hex-5-enamide

  • Compound

    (S)-2-(2-(4-Chlorobenzylamino)-2-oxoethyl)pent-4-enoic acid

  • Compound

    (S)-2-Allyl-N4-(4-chlorobenzyl)-N1-((R)-2-hydroxy-2-phenylethyl)succinamide

  • Compound

    (R)-2-((S)-2-(2-(4-Chlorobenzylamino)-2-oxoethyl)pent-4-enamido)-1-phenylethyl pent-4-enoate

  • Compound

    (S)-N-Benzyl-3-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-N-(2-hydroxyethyl)hex-5-enamide

  • Compound

    (S)-N-Benzyl-3-((R)-4-benzyl-2-oxooxazolidine-3-carbonyl)-N-(2-(triisopropylsilyloxy)ethyl)hex-5-enamide

  • Compound

    (S)-2-(2-(Benzyl(2-(triisopropylsilyloxy)ethyl)amino)-2-oxoethyl)pent-4-enoic acid

  • Compound

    (S)-2-Allyl-N4-benzyl-N1-((S)-1-hydroxypropan-2-yl)-N4-(2-(triisopropylsilyloxy)ethyl)succinamide

  • Compound

    (S)-((10S,13S)-10-Allyl-7-benzyl-3,3-diisopropyl-2,13-dimethyl-8,11-dioxo-4-oxa-7,12-diaza-3 silatetradecan-14-yl) 2-(tert-butoxycarbonylamino)hex-5-enoate

  • Compound

    tert-Butyl (3S,6S,12S,E)-6-(2-(benzyl(2-(triisopropylsilyloxy)ethyl)amino)-2-oxoethyl)-3-methyl-5,13-dioxo-1-oxa-4-azacyclotridec-8-en-12-ylcarbamate

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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.

Author information

Author notes

    • Benjamin Z Stanton
    •  & Lee F Peng

    These authors contributed equally to this work.

Affiliations

  1. The Howard Hughes Medical Institute at the Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, 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, Massachusetts 02138, USA.

    • Benjamin Z Stanton
    • , Lee F Peng
    • , Kazuo Nakai
    •  & Stuart L Schreiber
  3. Gastrointenstinal Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

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

    • Joel M Hyman
    •  & James K Chen
  5. Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.

    • Sam W Lee
    •  & Anna Mandinova
  6. Department of Stem Cell and Regenerative Biology, Harvard University, 42 Church Street, Cambridge, Massachusetts 02138, USA.

    • Julia L Fox

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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.

Corresponding authors

Correspondence to Lee F Peng or Stuart L Schreiber.

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    Supplementary Figures 1 and 2 and Supplementary Methods

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DOI

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

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