Molecular Formula | C21H17ClF2N4O2 |
Molar Mass | 430.84 |
Density | 1.434±0.06 g/cm3(Predicted) |
Boling Point | 614.7±55.0 °C(Predicted) |
pKa | 6.03±0.35(Predicted) |
Storage Condition | -20℃ |
In vitro study | In mutant p.G12C cancer cells, ARS-1620 covalently inhibited KRAS (G12C) activity with high potency and inhibition isomerization. ARS-1620 can rapidly occupy the G12C site in a concentration-dependent and time-dependent manner, exerting covalent inhibition. In cell lines containing this mutant allele, the TE50 value for target G12C ARS-1620 was approximately 0.3 μm. After 2 hours of 3 μm ARS-1620 treatment, the G12C was almost completely occupied. At H358 (p. In G12C) cells, ARS-1620 selectively inhibited phosphorylation of RAS-GTP and MEK, ERK, RSK, S6, and AKT in a concentration-dependent manner, but in the negative control group (lacking p.G12C lung cancer cell line; A549, H460 and H441 cells) did not have this activity. ARS-1620 is specific for the activity of the G12C allele, mediated by Cys-12 covalent modification. |
In vivo study | In mice, ARS-1620 had good oral bioavailability with F>60%. In a MIA-PaCa2 xenograft model carrying the p.G12C mutation, ARS-1620 inhibited tumor growth in a concentration-dependent manner, with significant regression at a concentration of 200 mg/kg/day. In a patient-derived tumor model, ARS-1620 selectively induced tumor regression. In H441 (p.G12V) transplanted tumor, ARS-1620 had no effect. The ARS-1620 R-atropisomer had no active effect in either model. ARS-1620 selectively induces tumor regression in patient-derived xenografts (PDX) with KRAS p.G12C mutation. |
1mg | 5mg | 10mg | |
---|---|---|---|
1 mM | 2.321 ml | 11.605 ml | 23.21 ml |
5 mM | 0.464 ml | 2.321 ml | 4.642 ml |
10 mM | 0.232 ml | 1.161 ml | 2.321 ml |
5 mM | 0.046 ml | 0.232 ml | 0.464 ml |