ARS-853 is a selective, covalent inhibitor of KRAS G12C, featuring an IC50 of 2.5 μM. By attaching to the GDP-bound form of the mutant KRAS oncoprotein, ARS-853 blocks its activation, thereby inhibiting KRAS-driven signaling pathways[1].[2].
体外研究
In experiments with KRASG12C-mutant lung cancer cells, ARS-853, at a concentration of 10 μM, dramatically reduces GTP-bound KRAS levels by over 95%. Its inhibition of cell proliferation, with an IC50 mirroring that for its target binding, alongside its suppression of effector signaling and induction of apoptosis in certain KRASG12C mutant cell lines, highlights its selective action against KRASG12C mutations without affecting non-mutant models[1].
ARS-853 inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation[2].
作用机制
ARS-853 covalently inhibits KRAS G12C and targets the GDP-bound, inactives state and prevents subsequent activation.[1][2]
ARS-853 细胞实验
Cell Line
Concentration
Treated Time
Description
References
KRASCCLW (KRASG12C/C51S/C80L/C118S/Y137W)
5 μM
0.2-1 seconds and 100-1000 seconds
Stopped-flow kinetic studies of ARS-853 interaction with KRASCCLW revealed fast binding (Kd = 36.0 ± 0.7 μM) and slow ligation (pKa = 8.21 ± 0.09).
J Biol Chem. 2022 Aug;298(8):102186.
KRAS G12C mutant
50 μM KRAS : 400 μM ARS-853
recorded every 15 or 30 minutes
Monitor the binding rate of ARS-853 to KRAS G12C, showing the rate constant of ARS-853 modification was 6.40 × 10−3 min−1, almost identical to the GTP hydrolysis rate
Sci Rep. 2023 Nov 7;13(1):19253.
HEK293 cells
10 μM
5 hours
ARS853 reduced GTP-bound KRASG12C levels but had no effect on KRASG12C/A59G.
Science. 2016 Feb 5;351(6273):604-8.
KRASG12C-mutant lung cancer cells (H358)
10 μM
24 hours
ARS853 induced apoptosis in four KRASG12C mutant cell lines.
Science. 2016 Feb 5;351(6273):604-8.
KRASG12C-mutant lung cancer cells (H358)
2.5 μM
72 hours
ARS853 inhibited proliferation with an IC50 of 2.5 μM, similar to its IC50 for target inhibition.
Science. 2016 Feb 5;351(6273):604-8.
HEK293 cells
10 μM
5 hours
ARS853 inhibited KRASG12C-GTP levels but had no effect on KRASG12C/A59G.
Science. 2016 Feb 5;351(6273):604-8
H358 cells
10 μM
5 hours
ARS853 reduced the level of GTP-bound KRAS by more than 95% and caused decreased phosphorylation of CRAF, ERK, and AKT.
Science. 2016 Feb 5;351(6273):604-8
ARS-853 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NIH 3T3 cells
Cell culture treatment
25, 50, 75, and 100 μM
15 minutes
Detection of intracellular oxidation of KRASG12C, showing H2O2 treatment shifts most protein to -SO2H state, blocking inhibitor binding.
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