SIR2446

**SIR2446** is a potent, selective, oral small molecule inhibitor of receptor-interacting serine/threonine-protein kinase 1 (**RIPK1**), a key regulator of inflammation, apoptosis, and necroptosis activated by pro-inflammatory cytokines like TNF-α or pathogens. Developed by **Sironax**, it demonstrated strong inhibitory activity in preclinical in vitro assays, cell necroptosis models, and a SIRS mouse model where it reduced TNF-α-induced hypothermia and cytokine storm dose-dependently. In a Phase I trial (single doses up to 600 mg, multiple up to 400 mg for 10 days), the magnesium salt form **SIR2446M** was well-tolerated with mild/moderate TEAEs (e.g., headache, vascular access pain, rash), favorable PK (T_max 1-3 h, half-life 11-19 h, minimal renal excretion, no marked accumulation), and robust PD with ~90-95% target engagement in PBMCs ex vivo, supporting advancement for degenerative and inflammatory diseases including potential CNS indications.[1][2][3][5][6][10]