Identification of SENP1 inhibitors through in silico screening and rational drug design
Yaxue Zhao1, Zhongli Wang1, Jianchen Zhang1
1State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.
Abstract:
The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening. Based on these scaffolds, a series of new compounds were designed and synthesized in order to improve their SENP1 inhibitory potency. As a result, compounds with IC50 as low as 3.5 μM (compound 13m) were obtained and a preliminary structure-activity relationship was discussed.
Insights
Researchers identified novel small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) inhibitors through in silico screening and synthesis. Compound 13m demonstrated potent SENP1 inhibition, offering potential for cancer therapeutics.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) regulate SUMOylation.
- SENP1, a key isoform, is implicated in prostate and colon cancers, making it a therapeutic target.
Purpose of the Study:
- To identify and develop novel inhibitors of SENP1.
- To explore potential therapeutic strategies for SENP1-related cancers.
Main Methods:
- In silico screening to identify initial SENP1 inhibitor scaffolds.
- Rational design and chemical synthesis of novel SENP1 inhibitor analogs.
- In vitro assays to determine inhibitory potency (IC50 values) and preliminary structure-activity relationship (SAR) analysis.
Main Results:
- Eleven diverse SENP1 inhibitor scaffolds were identified via in silico screening.
- Synthesized compounds showed improved SENP1 inhibitory activity.
- Compound 13m achieved an IC50 value as low as 3.5 μM.
Conclusions:
- Novel SENP1 inhibitors with significant potency were successfully developed.
- The identified compounds and preliminary SAR provide a foundation for further optimization.
- These findings highlight SENP1 as a promising target for developing new anti-cancer drugs.
