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Cancer Res. 2014 Sep 1;74(17):4811-21. doi: 10.1158/0008-5472.CAN-14-0317. Epub 2014 Jul 3.

Pyrvinium attenuates Hedgehog signaling downstream of smoothened.

Author information

1
Molecular Oncology Program, Department of Surgery, University of Miami, Miami, Florida.
2
Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Molecular Oncology Program, Department of Surgery, University of Miami, Miami, Florida. Sylvester Cancer Center, University of Miami, Miami, Florida.
4
Department of Cell and Developmental Biology and Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
5
StemSynergy Therapeutics Inc., Miami, Florida.
6
Weill Medical College, Cornell University, New York, New York.
7
Molecular Oncology Program, Department of Surgery, University of Miami, Miami, Florida. Sylvester Cancer Center, University of Miami, Miami, Florida. Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida.
8
Molecular Oncology Program, Department of Surgery, University of Miami, Miami, Florida. Sylvester Cancer Center, University of Miami, Miami, Florida. Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida. drobbins@med.miami.edu.

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.

PMID:
24994715
PMCID:
PMC4321822
DOI:
10.1158/0008-5472.CAN-14-0317
[Indexed for MEDLINE]
Free PMC Article

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