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

Williams CH, Hempel JE, Hao J, Frist AY, Williams MM, Fleming JT, Sulikowski GA, Cooper MK, Chiang C, Hong CC
Cell Rep. 2015 11 (1): 43-50

PMID: 25818300 · PMCID: PMC4394042 · DOI:10.1016/j.celrep.2015.03.001

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.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (14)

Animals Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotide Phosphodiesterases, Type 4 Hedgehog Proteins Phosphodiesterase 4 Inhibitors Pyrimidinones Receptors, G-Protein-Coupled Signal Transduction Small Molecule Libraries Smoothened Receptor Thiophenes Transcriptional Activation Zebrafish Zebrafish Proteins

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