Pyrvinium attenuates Hedgehog signaling downstream of smoothened.

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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 17 Pg. 4811-21 (Sep 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24994715 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Hedgehog Proteins
• Oncogene Proteins
• Pyrvinium Compounds
• Receptors, G-Protein-Coupled
• Trans-Activators
• Transcription Factors
• Zinc Finger Protein GLI1
• pyrvinium
• Casein Kinase Ialpha

Topics

• Animals
• Carcinoma, Basal Cell (drug therapy, metabolism)
• Casein Kinase Ialpha (metabolism)
• Cell Line
• HEK293 Cells
• Hedgehog Proteins (metabolism)
• Humans
• Medulloblastoma (drug therapy, metabolism)
• Mice
• Mice, Nude
• NIH 3T3 Cells
• Oncogene Proteins
• Pyrvinium Compounds (pharmacology)
• Receptors, G-Protein-Coupled (metabolism)
• Signal Transduction (drug effects)
• Trans-Activators
• Transcription Factors (metabolism)
• Zinc Finger Protein GLI1