Discovery of a Dual SENP1 and SENP2 Inhibitor

SUMOylation is a reversible post-translational modification (PTM) involving covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. Dysregulation of SUMOylation and deSUMOylation results in cellular malfunction and is linked to various diseases, such as cancer. Sentrin-specific proteases (SENPs) were identified for the maturation of SUMOs and the deconjugation of SUMOs from their substrate proteins. Hence, this is a promising target tackling the dysregulation of the SUMOylation process. Herein, we report the discovery of a novel protein-protein interaction (PPI) inhibitor for SENP1-SUMO1 by virtual screening and subsequent medicinal chemistry optimization of the hit molecule. The optimized inhibitor ZHAWOC8697 showed IC50 values of 8.6 mu M against SENP1 and 2.3 mu M against SENP2. With a photo affinity probe the SENP target was validated. This novel SENP inhibitor represents a new valuable tool for the study of SUMOylation processes and the SENP-associated development of small molecule-based treatment options.

Automated summary

SUMOylation, a reversible post-translational modification, involves covalent attachment of SUMO proteins to substrate proteins. Dysregulation of this process is linked to diseases like cancer. This study reports the discovery of a novel inhibitor for SENP1-SUMO1 interaction and validates its target. This finding is valuable for the study of SUMOylation processes and the development of treatment options.