These integrated results, spanning virtual screening to in vivo validation, identify Compound 7 as a promising lead compound. The study establishes a solid foundation for developing novel SIRT2 inhibitors as both chemical probes and potential therapeutics for SIRT2-driven NSCLC.

In conclusion, Doxorubicin was observed to induce EMT6 apoptosis through the inhibition of SIRT2 and RelA proteins. The outcomes of both experimental and bioinformatic studies provide a novel perspective on the biological effects of doxorubicin and underscore the potential of inhibiting the SIRT2-RelA axis as a promising biological target for cancer therapy.

Scratch-wound assays also revealed that SIRT2 inhibition led to polarity defects in the MDA-MB-231 cells, while in vitro space-restrictive invasion assays highlighted their reduced migratory capacity upon AGK2 treatment. Taken together, our findings suggest that SIRT2 inhibition promotes a perinuclear cytoskeletal organisation in MDA-MB-231 cells, which enhances their nuclear rigidity and impedes their invasion through confined spaces in vitro.

External validation parameters of the selectivity models confirmed their predictive power. Ultimately, the integration of 3D-QSAR, selectivity models and prediction of ADMET properties facilitated the identification of the most promising selective SIRT2 inhibitors for further development.

IBC alleviated TNBC by targeting SIRT2 and triggering the reactive oxygen species ROS/β-catenin/CDK2 axis. It is a promising natural lead compound for future development of SIRT2-targeting drugs.

Our structure-activity relationship (SAR) study has revealed that 2,3-constrained (S)-isomers possess enhanced in vitro enzymatic inhibitory activity against SIRT2 and retain excellent selectivity over SIRT1 and SIRT3, provided that a suitable ring A is used. This current study further explores SIRT2 inhibitors based on the 3-aminobenzyloxy nicotinamide scaffold and contributes to the discovery of potent, selective SIRT2 inhibitors that have been actively pursued for their potential therapeutic applications.

Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.

These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

Taken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

Our findings indicate that SIRT2 inhibition selectively targets ATRX-deficient gliomas for senescence through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.