GS-444217

GS-444217 is a potent, orally available and selective ATP-competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with an IC₅₀ of 2.87 nM^[1]. IC50 & Target:ASK1^[1] In Vitro: Treatment with GS-444217 reduces ASK1 phosphorylation and prevents the phosphorylation of MKK3/6, MKK4, p38, and JNK at concentrations of 0.3 μM and above with full suppression of ASK1 activity at 1 μM. GS-444217 (1 μM) reduces ASK1 activity within 5 minutes of addition to the cultures, reaching a maximum level of inhibition by 30 minutes. Removal of GS-444217 from the cultures results in reactivation of ASK1 autophosphorylation within 10 minutes and near-complete recovery 2 hours after drug washout^[1]. In Vivo: GS-444217 reduces oxidative stress (OS)-induced ASK1 signaling in kidney and inhibits acute renal tubular injury in rats. GS-444217 (30 mg/kg) inhibits activation of ASK1, p38, and JNK in rat kidney. GS-444217 has an in vivo EC₅₀ of approximately 1.6 μM for inhibiting the ASK1 pathway in rodent kidney^[1].