Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Regulator of G protein signaling (RGS) proteins are crucial for regulating G protein-coupled receptor signaling and maintaining cell homeostasis.
• Dysregulated RGS protein expression is implicated in various pathologies, driving the search for small-molecule inhibitors.
• RGS17 is notably upregulated in several cancers, making it a target for therapeutic intervention.

Purpose of the Study:

• To identify small-molecule inhibitors of the RGS17 protein.
• To characterize the mechanism of inhibition and establish a structure-activity relationship (SAR) for RGS17 inhibitors.

Main Methods:

• Conducted a high-throughput screening (HTS) of over 60,000 small molecules to identify inhibitors of the RGS17-Gαo protein-protein interaction.
• Performed chemical and biochemical characterization of hit compounds.
• Synthesized and tested analogues to establish the SAR profile.

Main Results:

• Identified five hit compounds that inhibit the RGS17-Gαo interaction.
• Discovered that three hits decomposed into reactive products, providing insights into compound stability.
• Established the first SAR profile for a small-molecule inhibitor of RGS17.

Conclusions:

• The study successfully identified RGS17 inhibitors and characterized their properties, including decomposition pathways.
• The findings provide valuable tools and knowledge for future drug discovery efforts targeting RGS proteins.
• The established SAR profile is a critical step towards developing effective RGS17-targeted therapeutics for cancer and other diseases.