A Dual SIRT6/Classical HDAC Inhibitor with Integrated Antiproliferative, Antimigratory, and Pharmacokinetic Advantages Against Pancreatic Cancer

Pancreatic cancer (PC) is highly malignant, with a poor prognosis and high metastatic potential. Given the synergy between sirtuin 6 (SIRT6) and classical histone deacetylase (HDAC) in regulating epithelial−mesenchymal transition (EMT), dual-target inhibitors may offer improved antimetastatic therapy. The lead compound 11e suffers from poor metabolic stability, weak antiproliferative activity, and insufficient antimigratory capacity. Through pharmacophore merging and structural optimization, we obtained S20, which potently inhibits SIRT6 (IC50 = 3.903 μM) and classical HDACs (IC50 = 0.217 μM). In vitro, S20 was superior to 11e in antiproliferative activity and showed stronger antimigratory activity than SAHA, 11e, or their combination. Mechanistically, S20 modulated EMT-associated marker expression, increasing E-cadherin while decreasing N-cadherin, vimentin, and ZEB1. Its intravenous half-life (4.11 h) was 14.7-fold longer than 11e (0.28 h). In vivo, S20 dose-dependently suppressed liver metastasis with favorable safety. In summary, S20 exhibits comprehensive advantages in antiproliferative, antimigratory, and metabolic stability, providing a new strategy for antimetastatic drug development.