新型KRASG12C抑制剂VT198的药效学及药动学研究
Pharmacodynamic and pharmacokinetic studies of a novel KRASG12C inhibitor VT198
王美晴 1白虎成 2张枢 3李小川 1王廷春 2段小群1
作者信息
- 1. 桂林医学院,桂林 541000
- 2. 博济医药科技股份有限公司,广州 510000
- 3. 苏州旭辉检测有限公司,苏州 215000
- 折叠
摘要
目的:通过细胞和小鼠模型实验研究新型KRASG12C抑制剂VT198 的体内外抗肿瘤作用.建立VT198 和其阳性对照药MRTX849 的LC-MS/MS方法,研究VT198 在大鼠体内的药动学特征.方法:运用CTG发光法、Transwell迁移实验检测VT198 对KRASG12C突变的人非小细胞肺癌细胞NCI-H358 增殖及迁移的影响.建造裸小鼠肿瘤细胞系移植模型,口服给药后测定荷瘤鼠的体重及肿瘤体积.灌胃(ig)给予SD大鼠VT198 和其阳性对照药,建立LC-MS/MS方法测定大鼠血浆中的药物浓度,并计算药动学参数.结果:VT198的IC50为3.07 nmol·L-1,细胞迁移率为(36.39±1.87)%,体内肿瘤体积抑制率为124.56%.大鼠单次ig给药(剂量10 mg·kg-1)后,VT198 的Tmax为(3.33±1.15)h,Cmax为(627.67±102.94)ng·mL-1,AUC0-t为(3 805.33±1 167.07)h·ng·mL-1,阳性对照药的Tmax为(6.00±0.00)h,Cmax为(69.63±18.11)ng·mL-1,AUC0-t为(609.25±77.88)h·ng·mL-1.结论:体外细胞实验表明VT198 对NCI-H358 细胞具有生长抑制及迁移抑制作用,体内药效学实验表明其能够有效抑制肿瘤体积增长,体内药动学实验表明VT198 的吸收程度和速度优于阳性对照药MRTX849.VT198 作为治疗KRASG12C突变蛋白相关癌症的潜在药物,具有进一步研究的价值.
Abstract
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.
关键词
非小细胞肺癌/KRASG12C抑制剂/药效学/LC-MS/MS法/药动学Key words
non-small cell lung cancer/KRASG12C inhibitor/pharmacodynamics/LC-MS/MS/pharma-cokinetics引用本文复制引用
基金项目
广西科技重大专项资助项目(桂科AA22096025)
广西研究生教育创新计划项目(YCSW2023431)
出版年
2024
NETL
NSTL
万方数据