AZD4747 (AZD-4747) is a highly potent, selective, covalent and brain-penetrant inhibitor of KRAS G12C with IC50 of 15 nM.
AZD4747 forms the desired covalent bond to Cys12 of KRAS G12C mutant.
AZD4747 potently inhibits the phosphorylation of p90RSK and the growth of KRASG12C mutant tumor cell line NCI–H358 with IC50 of 12 nM in spheroid proliferation assays, but not the non-KRASG12C tumor cell lines A549 (G12S) and Calu-6 (Q61K).
AZD4747 (100, 30, and 10 mg/kg, daily oral) inhibits the growth of KRASG12C mutant H358 xenograft tumors.
AZD4747 demonstrates the potential for treatment CNS metastases.
