Novel Naphthyridones Targeting Pannexin 1 for Colitis Management

Area of Science:

• Cell biology
• Pharmacology
• Gastroenterology

Background:

• Pannexin 1 (PANX1) channels release signaling molecules involved in various diseases.
• Current PANX1 inhibitors lack specificity and efficacy, hindering therapeutic applications for conditions like inflammatory bowel disease (IBD).

Purpose of the Study:

• To identify and characterize a novel, specific inhibitor of Pannexin 1 (PANX1).
• To evaluate the therapeutic potential of the new PANX1 inhibitor in a preclinical model of inflammatory bowel disease (IBD).

Main Methods:

• Hit-to-lead optimization and structure-activity relationship analysis.
• Site-directed mutagenesis, cell thermal shift assays, and molecular docking to determine the binding site.
• Assessment of compound 12 efficacy in a dextran sodium sulfate (DSS)-induced mouse model of IBD.

Main Results:

• Compound 12, a naphthyridone, was identified as a potent PANX1 inhibitor (IC50 = 0.73 µm) with high specificity, not affecting LRRC8/SWELL1 channels.
• Compound 12 directly binds to the Trp74 residue of PANX1.
• Treatment with compound 12 significantly reduced colitis severity in the DSS-induced IBD mouse model.

Conclusions:

• Compound 12 represents a novel, specific inhibitor of Pannexin 1 (PANX1) with a defined mechanism of action.
• The identified binding site provides a basis for future drug design targeting PANX1.
• PANX1 inhibition presents a promising therapeutic strategy for inflammatory bowel disease (IBD).