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Structure-Guided Optimization and Biological Validation of 1,3,4-Thiadiazole-Based SIRT2 Inhibitors Reinforcing
Ahmet Bugra Aksel1, Fikriye Ozgencil1, Filiz Bakar-Ates2
1Department of Pharmaceutical Chemistry, SIRTeam Group, Faculty of Pharmacy, Gazi University, Ankara, Türkiye.
Drug Development Research
|March 10, 2026
Summary
Researchers designed novel 1,3,4-thiadiazole derivatives to inhibit SIRT2 (Sirtuin 2), a protein linked to cancer and other diseases. Compound ST132 demonstrated antiproliferative effects in breast cancer cells, validating its potential as a SIRT2 inhibitor.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Sirtuin 2 (SIRT2) is a deacetylase implicated in cancer progression and various pathologies.
- Previous efforts yielded SIRT2 inhibitors with micromolar activity.
- Optimization of these inhibitors is crucial for therapeutic development.
Purpose of the Study:
- To design and synthesize novel 1,3,4-thiadiazole derivatives as potential SIRT2 inhibitors.
- To evaluate the inhibitory activity and antiproliferative effects of the synthesized compounds.
- To elucidate the structural basis of SIRT2 inhibition using computational methods.
Main Methods:
- Molecular docking-guided drug design.
- Synthesis of 1,3,4-thiadiazole derivatives.
- In vitro SIRT inhibitory screening (IC50 determination).
- Cellular assays in MCF-7 breast cancer cells.
- Molecular dynamics (MD) and MM-GBSA simulations.
Main Results:
- Two compounds, ST131 and ST132, exhibited moderate SIRT2 inhibition (IC50 values of 8.95 and 6.62 µM, respectively).
- ST132 demonstrated antiproliferative activity against MCF-7 cells.
- ST132 treatment led to increased acetylated α-tubulin, a marker of SIRT2 inhibition.
- Computational analyses rationalized the structure-activity relationship and confirmed ST132-SIRT2 complex stability.
Conclusions:
- Novel 1,3,4-thiadiazole derivatives were successfully synthesized and evaluated as SIRT2 inhibitors.
- ST132 shows promising antiproliferative effects and SIRT2 inhibitory activity.
- Computational modeling provided insights into the binding interactions and stability of ST132 with SIRT2, guiding future drug design efforts.
