GS-444217 is a potent, orally bioavailable, and selective ATP-competitive inhibitor targeting ASK1, with an IC50 of 2.87 nM. GS-444217 administration leads to a reduction in ASK1 phosphorylation and inhibits the phosphorylation of MKK3/6, MKK4, p38, and JNK at concentrations starting from 0.3 μM, achieving complete suppression of ASK1 activity at 1 μM. The introduction of GS-444217 at 1 μM to cell cultures decreases ASK1 activity within 5 minutes, with the peak effect at 30 minutes. Removing GS-444217 results in the reactivation of ASK1 autophosphorylation within 10 minutes, with a near-full recovery observed 2 hours post-drug removal[1].
GS-444217 动物研究
Animal study
GS-444217 mitigates oxidative stress (OS)-triggered ASK1 signaling in the kidneys and prevents acute injury to renal tubules in rats. Administered at a dose of 30 mg/kg, GS-444217 suppresses the activation of ASK1, p38, and JNK in the rat kidney. In vivo, GS-444217 achieves an EC50 of around 1.6 μM for the inhibition of the ASK1 pathway in rodent kidneys[1].
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