Dual SIRT6/HDAC inhibitor S20 targets pancreatic cancer metastasis
- SIRT6 and classical HDACs cooperate in epithelial-mesenchymal transition, motivating a single molecule that hits both to curb metastasis.
- Merging pharmacophores and optimizing a lead with weak potency and poor metabolic stability produced S20.
- S20 outperformed the lead and SAHA in cell migration, shifted EMT markers toward an epithelial state, and had a much longer intravenous half-life.
- In mice it dose-dependently reduced liver metastasis with a favorable safety profile.
💡 Points Based on the abstract
Merging a NAD-dependent sirtuin pharmacophore with a zinc-binding HDAC one is a hard polypharmacology brief, and the molecule risks bloat. Without matched single-target controls I can't tell which arm drives the reduced liver metastasis, so I'd separate SIRT6 from HDAC inhibition cleanly before trusting the dual rationale.
📄 Paper · Journal of Medicinal Chemistry ↗ A Dual SIRT6/Classical HDAC Inhibitor with Integrated Antiproliferative, Antimigratory, and Pharmacokinetic Advantages Against Pancreatic Cancer