Oral STING inhibitor D4 protects against severe acute pancreatitis in mice
- SAR work identified D4, which binds STING directly and blocks its oligomerization and downstream TBK1/IRF3 signalling.
- In macrophages it restored phagocytosis, autophagic flux and mitochondrial function while dampening NLRP3-linked pyroptosis.
- D4 was orally exposed and well tolerated at high dose, and cut pancreatic injury and enzyme levels in a caerulein/LPS model; STING knockdown looked similar.
💡 Points
Most STING programs chase agonists for oncology; an orally available inhibitor for an acute inflammatory indication is a different bet. The knockdown phenocopy is reassuring on mechanism, but I'd want to know how it behaves across species, since STING ligand pockets are notoriously species-dependent, and whether an acute dosing window is realistic in patients.
Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis ↗