Discovery of a Dual SENP1 and SENP2 Inhibitor

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• SUMOylation is a critical post-translational modification (PTM) regulating cellular functions.
• Dysregulation of SUMOylation and deSUMOylation is implicated in various diseases, including cancer.
• Sentrin-specific proteases (SENPs) are key enzymes involved in SUMO maturation and deconjugation, making them attractive therapeutic targets.

Purpose of the Study:

• To discover and optimize novel small molecule inhibitors targeting the SENP1-SUMO1 interaction.
• To develop chemical probes for studying the role of SENPs in biological processes.
• To explore new therapeutic strategies for diseases associated with SUMOylation dysregulation.

Main Methods:

• Virtual screening to identify initial hit compounds.
• Medicinal chemistry optimization to enhance inhibitor potency and specificity.
• Biochemical assays to determine inhibitory concentrations (IC50).
• Photoaffinity labeling to validate target engagement.

Main Results:

• Discovery of a novel protein-protein interaction (PPI) inhibitor, ZHAWOC8697.
• ZHAWOC8697 demonstrated inhibitory activity against SENP1 (IC50 = 8.6 μM) and SENP2 (IC50 = 2.3 μM).
• Target engagement of SENPs was confirmed using a photoaffinity probe.

Conclusions:

• A novel small molecule inhibitor targeting SENPs was successfully developed.
• This inhibitor serves as a valuable tool for investigating SUMOylation pathways.
• The findings open avenues for developing small molecule-based treatments for SENP-associated diseases.