Biological Activity
ARS-1620 is an atropisomeric selective KRASG12C inhibitor with desirable pharmacokinetics.
In Vitro
ARS-1620 is an atropisomeric selective KRASG12C inhibitor with desirable pharmacokinetics. ARS-1620 exhibits complete growth suppression of p.G12C cell lines (IC50=150 nM) with relatively benign effects on control cell lines. It is found that ARS-1620 significantly reduces expression of the gene set in p.G12C mutant cells in a time-dependent manner but not in the p.G12S mutant cells. Following a 5-day treatment period, only a minority of G12C mutant cell lines are sensitive to ARS-1620 under monolayer culture conditions, whereas in 3D-spheroid conditions, ARS-1620 elicits a robust response (p=0.0140)[1].
In Vivo
Following a single oral dose or 5 consecutive daily doses, ARS-1620 yields average peak tumor concentrations of 1.5 μM (50 mg/kg) and 5.5 μM (200 mg/kg), respectively, that enables significant KRASG12C target occupancy (>=70% G12C-TE at 200 mg/kg) for >24 hr. In MIAPaCa2 xenografts (p.G12C), ARS-1620 significantly inhibits tumor growth (p<0.001) in a dose-dependent manner with marked regression at a dose of 200 mg/kg, given once daily. Across all tumor models employed, ARS-1620 is well tolerated over the entire 3-week treatment period. Moreover, there are no observed clinical signs or toxicity of ARS-1620 in CD-1 mice even at oral doses up to 1,000 mg/kg administered daily over a 7-day period.
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.