Pyrvinium attenuates hedgehog signaling downstream of smoothened

Bin Li, Dennis Liang Fei, Colin A. Flaveny, Nadia Dahmane, Valérie Baubet, Zhiqiang Wang, Feng Bai, Xin-Hai Pei, Jezabel Rodriguez-Blanco, Brian Hang, Darren Orton, Lu Han, Baolin Wang, Anthony J Capobianco, Ethan Lee, David J Robbins

Research output: Contribution to journalArticle

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Abstract

The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers.

Original languageEnglish
Pages (from-to)4811-4821
Number of pages11
JournalCancer Research
Volume74
Issue number17
DOIs
StatePublished - Sep 1 2014

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Hedgehogs
HhAntag691
Casein Kinase I
Pyrvinium Compounds
Neoplasms
Transcription Factors
Enterobius
Medulloblastoma
Critical Pathways
Basal Cell Carcinoma
Drug Industry
pyrvinium
Inhibitory Concentration 50
Biomarkers
Observation
Clinical Trials
Recurrence
Mutation
Growth

Cite this

Li, B., Fei, D. L., Flaveny, C. A., Dahmane, N., Baubet, V., Wang, Z., ... Robbins, D. J. (2014). Pyrvinium attenuates hedgehog signaling downstream of smoothened. Cancer Research, 74(17), 4811-4821. https://doi.org/10.1158/0008-5472.CAN-14-0317

Pyrvinium attenuates hedgehog signaling downstream of smoothened. / Li, Bin; Fei, Dennis Liang; Flaveny, Colin A.; Dahmane, Nadia; Baubet, Valérie; Wang, Zhiqiang; Bai, Feng; Pei, Xin-Hai; Rodriguez-Blanco, Jezabel; Hang, Brian; Orton, Darren; Han, Lu; Wang, Baolin; Capobianco, Anthony J; Lee, Ethan; Robbins, David J.

In: Cancer Research, Vol. 74, No. 17, 01.09.2014, p. 4811-4821.

Research output: Contribution to journalArticle

Li, B, Fei, DL, Flaveny, CA, Dahmane, N, Baubet, V, Wang, Z, Bai, F, Pei, X-H, Rodriguez-Blanco, J, Hang, B, Orton, D, Han, L, Wang, B, Capobianco, AJ, Lee, E & Robbins, DJ 2014, 'Pyrvinium attenuates hedgehog signaling downstream of smoothened', Cancer Research, vol. 74, no. 17, pp. 4811-4821. https://doi.org/10.1158/0008-5472.CAN-14-0317
Li B, Fei DL, Flaveny CA, Dahmane N, Baubet V, Wang Z et al. Pyrvinium attenuates hedgehog signaling downstream of smoothened. Cancer Research. 2014 Sep 1;74(17):4811-4821. https://doi.org/10.1158/0008-5472.CAN-14-0317
Li, Bin ; Fei, Dennis Liang ; Flaveny, Colin A. ; Dahmane, Nadia ; Baubet, Valérie ; Wang, Zhiqiang ; Bai, Feng ; Pei, Xin-Hai ; Rodriguez-Blanco, Jezabel ; Hang, Brian ; Orton, Darren ; Han, Lu ; Wang, Baolin ; Capobianco, Anthony J ; Lee, Ethan ; Robbins, David J. / Pyrvinium attenuates hedgehog signaling downstream of smoothened. In: Cancer Research. 2014 ; Vol. 74, No. 17. pp. 4811-4821.
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