The novel SIRT2-targeted PROTAC degraders as the efficient agents for the treatment of ovarian cancer.

Ovarian cancer is a highly lethal gynecological malignancy that poses a significant threat to women's health. Current treatments for patients with clinical recurrence and drug resistance are limited, underscoring the urgent need for new therapeutic strategies. SIRT2, one subtype of sirtuin protein family, has been shown to promote tumor cell proliferation, migration, and invasion by regulating multiple signaling pathways through deacetylation. In this study, we discovered that knockdown of SIRT2 significantly inhibited the migration and invasion of ovarian cancer cells. To develop targeted therapies, we designed and synthesized a series of SIRT2-targeted PROTACs based on the small molecule inhibitor Tenovin-6. These PROTACs exhibited potent SIRT2 degradation capability and significant anti-proliferative activity in several ovarian cancer cell lines. Among them, W10 demonstrated the most potent anti-proliferative activity both in vitro and in vivo, with an IC50 value of 0.08 ± 0.04 μmol/L and a selectivity index (SI) of 33.00. W10 significantly suppressed clonogenic formation and migration, induced cell cycle arrest, and promoted apoptosis. Mechanistically, W10 inhibited the AKT/mTOR signaling pathway by indirectly degrading SIRT2 and blocking downstream protein phosphorylation, thereby disrupting the signaling cascade and suppressing tumor development.