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.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cyclic AMP-Dependent Protein Kinases / biosynthesis*
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
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Hedgehog Proteins / antagonists & inhibitors
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Hedgehog Proteins / genetics
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Phosphodiesterase 4 Inhibitors / administration & dosage*
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Phosphodiesterase 4 Inhibitors / chemistry
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Phosphodiesterase 4 Inhibitors / isolation & purification
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Pyrimidinones / chemistry*
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / genetics*
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Signal Transduction / drug effects
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Small Molecule Libraries / administration & dosage
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Small Molecule Libraries / chemistry
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Smoothened Receptor
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Thiophenes / chemistry*
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Transcriptional Activation / drug effects
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Zebrafish
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Zebrafish Proteins / antagonists & inhibitors
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Zebrafish Proteins / genetics*
Substances
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Hedgehog Proteins
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Phosphodiesterase 4 Inhibitors
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Pyrimidinones
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Receptors, G-Protein-Coupled
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Small Molecule Libraries
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Smoothened Receptor
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Thiophenes
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Zebrafish Proteins
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eggmanone
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smo protein, zebrafish
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Cyclic AMP-Dependent Protein Kinases
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Cyclic Nucleotide Phosphodiesterases, Type 4