Discovery and Optimization of a Porcupine Inhibitor.
Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and function. The inhibition of PORCN could serve as a therapeutic approach for the treatment of a number of Wnt-dependent cancers. Herein, we describe the identification of a Wnt secretion inhibitor from cellular high throughput screening. Classical SAR based cellular optimization provided us with a PORCN inhibitor with nanomolar activity and excellent bioavailability that demonstrated efficacy in a Wnt-driven murine tumor model. Finally, we also discovered that enantiomeric PORCN inhibitors show very different activity in our reporter assay, suggesting that such compounds may be useful for mode of action studies on the PORCN O-acyltransferase.
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Related Subject Headings
- Wnt Signaling Pathway
- Structure-Activity Relationship
- Models, Molecular
- Membrane Proteins
- Medicinal & Biomolecular Chemistry
- Enzyme Inhibitors
- Drug Discovery
- Acyltransferases
- 3405 Organic chemistry
- 3404 Medicinal and biomolecular chemistry
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Wnt Signaling Pathway
- Structure-Activity Relationship
- Models, Molecular
- Membrane Proteins
- Medicinal & Biomolecular Chemistry
- Enzyme Inhibitors
- Drug Discovery
- Acyltransferases
- 3405 Organic chemistry
- 3404 Medicinal and biomolecular chemistry