KRAS is one of the most frequently mutated oncogenes in cancer. KRASG12C mutations are present in lung and colon adenocarcinoma as well as smaller fractions of other cancers. MRTX849 is a potent, selective, and covalent KRASG12C inhibitor. MRTX849 demonstrated much greater modification of KRASG12C when preloaded with GDP compared with GTP supporting that MRTX849 binds to and stabilizes the inactive GDP-bound form of KRASG12C. In the KRASG12C-mutant H358 lung and MIA PaCa-2 pancreatic cancer cell lines, MRTX849 demonstrated an upward electrophoretic mobility shift of KRASG12C protein band migration by immunoblot, indicative of covalent modification of KRASG12C. MRTX849 potently inhibited cell growth in the vast majority of KRASG12C-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 KRASG12C 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 pS6S235/36 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[1].
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