PUBLICATION

An In Vivo Chemical Genetic Screen Identifies Phosphodiesterase 4 as a Pharmacological Target for Hedgehog Signaling Inhibition

Authors
Williams, C.H., Hempel, J.E., Hao, J., Frist, A.Y., Williams, M.M., Fleming, J.T., Sulikowski, G.A., Cooper, M.K., Chiang, C., Hong, C.C.
ID
ZDB-PUB-150331-13
Date
2015
Source
Cell Reports   11(1): 43-50 (Journal)
Registered Authors
Hong, Charles
Keywords
none
MeSH Terms
  • Hedgehog Proteins/antagonists & inhibitors
  • Hedgehog Proteins/genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 4/genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism*
  • Thiophenes/chemistry*
  • Signal Transduction/drug effects
  • Small Molecule Libraries/administration & dosage
  • Small Molecule Libraries/chemistry
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/genetics*
  • Animals
  • Cyclic AMP-Dependent Protein Kinases/biosynthesis*
  • Cyclic AMP-Dependent Protein Kinases/genetics
  • Phosphodiesterase 4 Inhibitors/administration & dosage*
  • Phosphodiesterase 4 Inhibitors/chemistry
  • Phosphodiesterase 4 Inhibitors/isolation & purification
  • Zebrafish
  • Pyrimidinones/chemistry*
  • Transcriptional Activation/drug effects
  • Receptors, G-Protein-Coupled/antagonists & inhibitors
  • Receptors, G-Protein-Coupled/genetics*
(all 22)
PubMed
25818300 Full text @ Cell Rep.
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.
Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
No data available
Human Disease / Model
No data available
Sequence Targeting Reagents
No data available
Fish
No data available
Antibodies
Orthology
No data available
Engineered Foreign Genes
No data available
Mapping
No data available
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Citation
Williams, C.H., Hempel, J.E., Hao, J., Frist, A.Y., Williams, M.M., Fleming, J.T., Sulikowski, G.A., Cooper, M.K., Chiang, C., Hong, C.C. (2015) An In Vivo Chemical Genetic Screen Identifies Phosphodiesterase 4 as a Pharmacological Target for Hedgehog Signaling Inhibition. Cell Reports. 11(1):43-50.