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
-
- Animals
- Cyclic AMP-Dependent Protein Kinases/biosynthesis*
- Cyclic AMP-Dependent Protein Kinases/genetics
- Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry
- Cyclic Nucleotide Phosphodiesterases, Type 4/genetics
- Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism*
- Hedgehog Proteins/antagonists & inhibitors
- Hedgehog Proteins/genetics
- Phosphodiesterase 4 Inhibitors/administration & dosage*
- Phosphodiesterase 4 Inhibitors/chemistry
- Phosphodiesterase 4 Inhibitors/isolation & purification
- Pyrimidinones/chemistry*
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Receptors, G-Protein-Coupled/genetics*
- Signal Transduction/drug effects
- Small Molecule Libraries/administration & dosage
- Small Molecule Libraries/chemistry
- Thiophenes/chemistry*
- Transcriptional Activation/drug effects
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics*
- PubMed
- 25818300 Full text @ Cell Rep.
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping