Skip to main content

Thank you for visiting nature.com. 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.

  • Brief Communication
  • Published:

Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling

Nature Chemical Biology volume 9, pages 247–249 (2013)Cite this article

Subjects

Abstract

Inhibition of Sonic hedgehog (Shh) signaling is of great clinical interest. Here we exploit Hedgehog acyltransferase (Hhat)-mediated Shh palmitoylation, a modification critical for Shh signaling, as a new target for Shh pathway inhibition. A target-oriented high-throughput screen was used to identify small-molecule inhibitors of Hhat. In cells, these Hhat inhibitors specifically block Shh palmitoylation and inhibit autocrine and paracrine Shh signaling.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: RU-SKI 43 inhibits Hhat.
Figure 2: RU-SKI 43 blocks Shh signaling.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Fuccillo, M., Joyner, A.L. & Fishell, G. Nat. Rev. Neurosci. 7, 772–783 (2006).

    Article  CAS  Google Scholar 

  3. Barakat, M.T., Humke, E.W. & Scott, M.P. Trends Mol. Med. 16, 337–348 (2010).

    Article  CAS  Google Scholar 

  4. Mann, R.K. & Beachy, P.A. Annu. Rev. Biochem. 73, 891–923 (2004).

    Article  CAS  Google Scholar 

  5. Buglino, J.A. & Resh, M.D. J. Biol. Chem. 283, 22076–22088 (2008).

    Article  CAS  Google Scholar 

  6. Goetz, J.A., Singh, S., Suber, L.M., Kull, F.J. & Robbins, D.J. J. Biol. Chem. 281, 4087–4093 (2006).

    Article  CAS  Google Scholar 

  7. Chen, M.H., Li, Y.J., Kawakami, T., Xu, S.M. & Chuang, P.T. Genes Dev. 18, 641–659 (2004).

    Article  CAS  Google Scholar 

  8. Hofmann, K. Trends Biochem. Sci. 25, 111–112 (2000).

    Article  CAS  Google Scholar 

  9. Buglino, J.A. & Resh, M.D. PLoS ONE 5, e11195 (2010).

    Article  Google Scholar 

  10. Liang, X. et al. J. Biol. Chem. 276, 30987–30994 (2001).

    Article  CAS  Google Scholar 

  11. Peseckis, S.M., Deichaite, I. & Resh, M.D. J. Biol. Chem. 268, 5107–5114 (1993).

    CAS  PubMed  Google Scholar 

  12. Janda, C.Y., Waghray, D., Levin, A.M., Thomas, C. & Garcia, K.C. Science 337, 59–64 (2012).

    Article  CAS  Google Scholar 

  13. Pan, S. et al. ACS Med. Chem. Lett. 1, 130–134 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Wu, X., Walker, J., Zhang, J., Ding, S. & Schultz, P.G. Chem. Biol. 11, 1229–1238 (2004).

    Article  CAS  Google Scholar 

  16. Yamaguchi, A., Komori, T. & Suda, T. Endocr. Rev. 21, 393–411 (2000).

    Article  CAS  Google Scholar 

  17. Rohatgi, R., Milenkovic, L., Corcoran, R.B. & Scott, M.P. Proc. Natl. Acad. Sci. USA 106, 3196–3201 (2009).

    Article  CAS  Google Scholar 

  18. Taylor, F.R. et al. Biochemistry 40, 4359–4371 (2001).

    Article  CAS  Google Scholar 

  19. Stanton, B.Z. et al. Nat. Chem. Biol. 5, 154–156 (2009).

    Article  CAS  Google Scholar 

  20. Peukert, S. & Miller-Moslin, K. ChemMedChem 5, 500–512 (2010).

    Article  CAS  Google Scholar 

  21. Testaz, S. et al. Proc. Natl. Acad. Sci. USA 98, 12521–12526 (2001).

    Article  CAS  Google Scholar 

  22. Chinchilla, P., Xiao, L., Kazanietz, M.G. & Riobo, N.A. Cell Cycle 9, 570–579 (2010).

    Article  CAS  Google Scholar 

  23. Metcalfe, C. & de Sauvage, F.J. Cancer Res. 71, 5057–5061 (2011).

    Article  CAS  Google Scholar 

  24. Donepudi, M. & Resh, M.D. Cell Signal. 20, 1359–1367 (2008).

    Article  CAS  Google Scholar 

  25. Wolven, A., Okamura, H., Rosenblatt, Y. & Resh, M.D. Mol. Biol. Cell 8, 1159–1173 (1997).

    Article  CAS  Google Scholar 

  26. Berthiaume, L. & Resh, M.D. J. Biol. Chem. 270, 22399–22405 (1995).

    Article  CAS  Google Scholar 

  27. Zhang, J.H., Chung, T.D. & Oldenburg, K.R. J. Biomol. Screen. 4, 67–73 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Louft-Nisenbaum, K. Anderson, D. Tan, E. Legué and A. Joyner for helpful input. This work was supported by US National Institutes of Health grants GM57966 and CA158474, Cycle for Survival, the Geoffrey Beene Cancer Research Foundation, the Sarcoma Foundation of America, W.H. Goodwin and A. Goodwin and the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center. The Organic Synthesis Core is partially supported by NCI P30 CA008748-43.

Author information

Authors and Affiliations

  1. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Elissaveta Petrova, Jessica Rios-Esteves & Marilyn D Resh

  2. Graduate Program in Pharmacology, Weill-Cornell Graduate School of Medical Sciences of Cornell University, New York, New York, USA

    Elissaveta Petrova

  3. Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Jessica Rios-Esteves & Marilyn D Resh

  4. Pharmacology Program, Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Ouathek Ouerfelli

  5. High-Throughput Screening Resource Center, Rockefeller University, New York, New York, USA

    J Fraser Glickman

  6. Graduate Program in Cell Biology, Weill-Cornell Graduate School of Medical Sciences of Cornell University, New York, New York, USA

    Marilyn D Resh

  7. Graduate Program in Biochemistry, Weill-Cornell Graduate School of Medical Sciences of Cornell University, New York, New York, USA

    Marilyn D Resh

Authors
  1. Elissaveta Petrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessica Rios-Esteves
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ouathek Ouerfelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Fraser Glickman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marilyn D Resh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.P. performed all experiments, except for Wnt acylation performed by J.R.-E. J.F.G. supervised the high-throughput screening performed by E.P., and hits were analyzed by E.P., O.O., J.F.G. and M.D.R. The research plan was designed by E.P., J.F.G. and M.D.R. E.P. and M.D.R. wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Marilyn D Resh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results (PDF 1690 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Petrova, E., Rios-Esteves, J., Ouerfelli, O. et al. Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling. Nat Chem Biol 9, 247–249 (2013). https://doi.org/10.1038/nchembio.1184

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.1184

This article is cited by

Search

Advanced search

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