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Cell Rep. 2015 Apr 7;11(1):43-50. doi: 10.1016/j.celrep.2015.03.001. Epub 2015 Mar 26.

An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition.

Author information

1
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
2
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA.
4
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
5
Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
6
Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
7
Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Research Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
8
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Research Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA. Electronic address: charles.c.hong@vanderbilt.edu.

Abstract

Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation.

PMID:
25818300
PMCID:
PMC4394042
DOI:
10.1016/j.celrep.2015.03.001
[Indexed for MEDLINE]
Free PMC Article

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