货号：M5249

储存条件：粉末-20°C可保存3年；液体-80°C可保存12月。

产品描述

KRAS is one of the most frequently mutated oncogenes in cancer. KRAS^G12C mutations are present in lung and colon adenocarcinoma as well as smaller fractions of other cancers. MRTX849 is a potent, selective, and covalent KRAS^G12C inhibitor. MRTX849 demonstrated much greater modification of KRAS^G12C when preloaded with GDP compared with GTP supporting that MRTX849 binds to and stabilizes the inactive GDP-bound form of KRAS^G12C. In the KRAS^G12C-mutant H358 lung and MIA PaCa-2 pancreatic cancer cell lines, MRTX849 demonstrated an upward electrophoretic mobility shift of KRAS^G12C protein band migration by immunoblot, indicative of covalent modification of KRAS^G12C. MRTX849 potently inhibited cell growth in the vast majority of KRAS^G12C-mutant cell lines with IC₅₀ values ranging between 10 and 973 nM in the 2D format and between 0.2 and 1042 nM in the 3D format. In vivo, the modified fraction of KRAS^G12C was 74% at 6 hours post-dose and gradually decreased to 47% by 72 hours after a single oral dose of MRTX849 at 30 mg/kg to H358 xenograft-bearing mice. To evaluate the effect of MRTX849 on KRAS-dependent signal transduction in vivo, a single dose of MRTX849 at 10, 30 or 100 mg/kg was administered to H358 tumor-bearing mice. Dose-dependent inhibition of ERK1/2 and pS6^S235/36 phosphorylation was observed at 6 hours post-dose. Finally, significant, dose-dependent, anti-tumor activity was observed at the 3, 10, 30 and 100 mg/kg dose levels of MRTX849 in the MIA PaCa-2 model.

产品信息