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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK293T cells
0.001–10 μM
2 hours
To evaluate the effect of GS-444217 to inhibit ASK1 autophosphorylation and ASK1-mediated signaling. GS-444217 reduced ASK1 phosphorylation and prevented 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.
J Clin Invest. 2018 Oct 1;128(10):4485-4500
Mouse cochlear explants
100 μM
24 hours
Evaluate the effect of high concentration GS-444217 on hair cell survival. Results showed that 100 μM GS-444217 did not significantly increase hair cell death.
J Mol Med (Berl). 2022 May;100(5):797-813
Mouse cochlear explants
1 μM
24 hours
Evaluate the inhibitory effect of GS-444217 on aminoglycoside-induced hair cell death. Results showed that 1 μM GS-444217 significantly attenuated neomycin-induced hair cell death.
J Mol Med (Berl). 2022 May;100(5):797-813
GS-444217 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Renal ischemia/reperfusion (I/R) injury model
Oral
30 mg/kg
Single dose
To assess the protective effect of GS-444217 against acute renal tubular injury. GS-444217 reduced serum creatinine and blood urea nitrogen, decreased tubular necrosis and apoptosis, and reduced mRNA expression of proinflammatory and profibrotic mediators.
J Clin Invest. 2018 Oct 1;128(10):4485-4500
Mice
Diabetic mouse model
Oral gavage
30 mg/kg/bid
Twice daily, from day 10 to day 28
GS-444217 treatment reduced the gene expression of Cdkn1a and Cdkn2a, and the number of Cdkn1a+ TEC in diabetic kidneys, and reduced urine excretion of Cdkn1a at day 28 after IRI.
Clin Sci (Lond). 2024 Mar 6;138(5):309-326
Mice
Nlrp3A350V/+CreT knock-in mice
Oral
0.2% in chow
Continued for 6 weeks
To evaluate the effect of ASK1 inhibition on liver fibrosis, showing significant reduction in liver cell death and fibrosis
JCI Insight. 2020 Jan 30;5(2):e123294
Mice
Tg26 mouse model
Oral
0.1% or 0.2%
6 weeks
GS-444217 attenuated the development of GS, podocyte loss, tubular injury, interstitial inflammation and renal fibrosis in Tg26 mice. These improvements were accompanied by a marked reduction in albuminuria and improved renal function.
Nephrol Dial Transplant. 2021 Feb 20;36(3):430-441
SD rats and WKY rats
Nephrotoxic serum nephritis (NTN) model
Oral gavage
30 mg/kg
Twice daily, until 1 hour before being killed (day 1 for SD rats, day 14 for WKY rats)
GS-444217 inhibited p38 and JNK signaling pathways, reducing kidney inflammation and fibrosis. In SD rats, GS-444217 prevented proteinuria and glomerular thrombosis with suppression of macrophage activation. In WKY rats, GS-444217 reduced crescent formation, prevented renal impairment and reduced proteinuria.
J Cell Mol Med. 2018 Sep;22(9):4522-4533
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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