RSC medicinal chemistryJul 30, 2026

Testing pyrazolo-pyrimidines as inhibitors of the SIRT2 enzyme using computer models and lab experiments

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Updated Aug 4, 2026

Abstract

Compounds 11 and 15 demonstrated SIRT2 IC50 values of 0.3 and 0.1 μM, respectively.

Sirtuins are involved in various biological pathways and may serve as targets for therapeutic agents in diseases like cancer and diabetes.
Novel selective SIRT2 inhibitors have been identified, with a focus on pyrazolo-pyrimidine compounds.
Previous compounds (1-5) exhibited SIRT2 inhibition rates up to 81.2% at 150 μM.
Newly developed analogues (6-16) showed improved SIRT2 inhibitory activity compared to earlier compounds.
Molecular modeling studies indicated similar interaction patterns between the new compounds and SIRT2.
Biochemical assays confirmed the efficacy of compounds 11 and 15 as potential anticancer agents.

Simplified

Sirtuins (SIRTs) involvement in different biological pathways opens a promising scenario for the development of related ligands to be evaluated as therapeutic agents in different diseases, such as cancer, neurodegenerative disorders, diabetes, cardiovascular and autoimmune diseases. The continuous elucidation of several SIRT2-ligand complexes fostered the discovery of novel and more selective SIRT2 inhibitors (SIRT2Is). Among them, SIRT2 in the presence of SirReal2 analogues was the most investigated. We recently reported pyrazolo-pyrimidine compounds (1-5) as SIRT2Is (1, SIRT2 % inhibition = 81.2%, at 150 μM). Herein, combined ligand- and structure-based approaches enabled us to filter a further series of pyrazolo-pyrimidine-based analogues (6-16) endowed with improved SIRT2 inhibitory activity in comparison to 1-5. The applied molecular modelling studies revealed superimposable molecular interaction fields (MIFs) and protein-ligand contacts compared with the reference SIRT2Is. Subsequent biochemical and biological assays validated the reported strategy and pointed to compounds 11 and 15 (SIRT2 IC₅₀ = 0.3 and 0.1 μM, respectively) as the most promising SIRT2Is, to be further investigated as anticancer agent.

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Testing pyrazolo-pyrimidines as inhibitors of the SIRT2 enzyme using computer models and lab experiments

Abstract

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