KRAS G12C-IN-74

KRAS G12C-IN-74 is an orally active, selective inhibitor of KRASG12C with a target IC50 of 43.18 nM. It induces G0/G1 cell cycle arrest and apoptosis (apoptosis) in cancer cells harboring the KRASG12C mutation. KRAS G12C-IN-74 is applicable for research in KRASG12C-mutant pancreatic cancer, colorectal cancer, and lung cancer.

KRas (G12C):43.18 nM

KRAS G12C-IN-74 (Compound 7q) effectively inhibits the proliferation of NCI-H358 3D cell spheroids with an IC50 of 0.42 nM over 7 days. Within 72 hours, it shows potent inhibition on KRAS G12C mutant cell lines, with IC50 values ranging from 0.42 nM (NCI-H358, 3D) to 3.331 μM (H1373), while exhibiting weaker effects on non-G12C KRAS mutant and wild-type cell lines. KRAS G12C-IN-74 (200-800 nM; 48 h) causes cell cycle arrest in the G0/G1 phase and induces apoptosis in NCI-H358 cells. In NCI-H1373 cells, KRAS G12C-IN-74 (1-8 μM; 48 h) induces dose-dependent apoptosis, significantly increasing apoptosis rates to 81.28% and 82.75% when combined with ML385 or RBN-2397, respectively, after 48 hours of incubation. Additionally, combining KRAS G12C-IN-74 (72 h) with the pan-USP inhibitor PR-619 drastically reduces the IC50 for intrinsic resistant NCI-H1373 cells from micromolar to nanomolar levels.

KRAS G12C-IN-74 (Compound 7q) exhibits potent and dose-dependent antitumor activity in the MIA PaCa-02 pancreatic cancer xenograft model at doses of 3-30 mg/kg administered orally once daily for 21 days. At a dose of 100 mg/kg, administered orally once daily for 21 days, it demonstrates strong antitumor activity in the SW837 colorectal cancer xenograft model. In the H1373 lung cancer xenograft model, KRAS G12C-IN-74 at 30-100 mg/kg, given orally once daily for 9-18 days, shows statistically significant but moderate single-agent activity, and demonstrates synergistic antitumor effects when combined with ML385, RBN-2397, or PR-619.