Pharmacodynamic and pharmacokinetic studies of a novel KRASG12C inhibitor VT198
Objective:To study the in vitro and in vivo anti-tumor effects of a novel KRASG12C inhibitor VT198 through cell and mouse model experiments and establish a LC-MS/MS method for determination of VT198 and its positive control drug MRTX849 to study the pharmacokinetic characteristics of VT198 in rats.Methods:The effects of VT198 on the proliferation and migration of KRASG12C mutated human non-small cell lung cancer cells(NCI-H358)were detected using CTG luminescence and Transwell migration experiments.A nude mouse tumor cell line transplantation model was constructed,and the body weight and tumor volume of tumor bearing mice were measured after oral administration of drugs.SD rats were given VT198 and MRTX849 by gavage,and an LC-MS/MS method was established to determine the drug concentration in rat plasma and pharmacokinetic parameters were calculated.Results:The IC50 of VT198 was 3.07 nmol·L-1,the cell migration rate was(36.39±1.87)%,and the in vivo tumor volume inhibition rate was 124.56%.After single-dose intragastric administration of 10 mg·kg-1 to rats,the Tmax of VT198 was(3.33±1.15)hours,Cmax was(627.67±102.94)ng·mL-1,AUC0-twas(3805.33±1167.07)h·ng·mL-1.For the positive control drug MRTX849,Tmax was(6.00±0.00)hours,Cmax was(69.63±18.11)ng·mL-1,and AUC0-t was(609.25±77.88)h·ng·mL-1.Conclusion:In vitro cell experiments have shown that VT198 has growth inhibition and migration inhibition effects on NCI-H358 cells.In vivo pharmacokinetic experiments have shown that it can effectively inhibit tumor volume growth.In vivo pharmacokinetic experiments have shown that VT198's absorption degree and speed are superior to the positive control drug MRTX849.VT198,as a potential drug for treating KRASG12C mutant protein related cancer,has further research value.
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