PUBLICATION
Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action
- Authors
- Hempel, J.E., Cadar, A.G., Hong, C.C.
- ID
- ZDB-PUB-160316-4
- Date
- 2016
- Source
- Bioorganic & medicinal chemistry letters 26(8): 1947-53 (Journal)
- Registered Authors
- Hong, Charles
- Keywords
- Eggmanone, Hedgehog signaling pathway, Phenotypic screening, Probe development, Suppressor of Fused
- MeSH Terms
-
- Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism*
- Dose-Response Relationship, Drug
- HEK293 Cells
- Hedgehog Proteins/antagonists & inhibitors*
- Humans
- Molecular Structure
- Phosphodiesterase 4 Inhibitors/chemical synthesis
- Phosphodiesterase 4 Inhibitors/chemistry
- Phosphodiesterase 4 Inhibitors/pharmacology*
- Pyrimidinones/chemical synthesis
- Pyrimidinones/chemistry
- Pyrimidinones/pharmacology*
- Repressor Proteins/antagonists & inhibitors
- Repressor Proteins/deficiency
- Signal Transduction/drug effects*
- Smoothened Receptor/antagonists & inhibitors
- Structure-Activity Relationship
- PubMed
- 26976215 Full text @ Bioorg. Med. Chem. Lett.
Citation
Hempel, J.E., Cadar, A.G., Hong, C.C. (2016) Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action. Bioorganic & medicinal chemistry letters. 26(8):1947-53.
Abstract
From a high content in vivo screen for modulators of developmental patterning in embryonic zebrafish, we previously identified eggmanone (EGM1, 3) as a Hedgehog (Hh) signaling inhibitor functioning downstream of Smoothened. Phenotypic optimization studies for in vitro probe development utilizing a Gli transcription-linked stable luciferase reporter cell line identified EGM1 analogs with improved potency and aqueous solubility. Mechanistic profiling of optimized analogs indicated two distinct scaffold clusters: PDE4 inhibitors able to inhibit downstream of Sufu, and PDE4-independent Hh inhibitors functioning between Smo and Sufu. Each class represents valuable in vitro probes for elucidating the complex mechanisms of Hh regulation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping