KRASG12C IN-17 is an orally active covalent inhibitor of KRASG12C, demonstrating potent inhibitory activity in KRASG12C-mutant cancer cells (NCI-H23 IC50 = 0.7 nM; NCI-H358 IC50 = 0.5 nM). It efficiently and irreversibly forms a covalent bond with KRASG12C in both GDP-bound and GMPPNP-bound states, with a modification rate exceeding 96%. KRASG12C IN-17 is applicable for research on KRAS-driven tumors, including colorectal cancer.

KRASG12C IN-17 (compound 19) effectively suppresses the proliferation of NCI-H23 and NCI-H358 cells with the KRAS G12C mutation, exhibiting IC 50 values of 0.7 nM and 0.5 nM, respectively, after 72-144 hours of treatment. It efficiently and irreversibly modifies KRAS G12C in both GDP-bound and GMPPNP-bound states, achieving a modification rate exceeding 96% within 15 minutes. In the Ba/F3 model, KRASG12C IN-17 effectively inhibits various drug-resistant KRAS G12C mutants, including R68S, H95Q, Y96C, and Q99L. It also shows antiproliferative activity in certain KRAS G12C secondary mutant cancer cell lines, particularly maintaining strong efficacy in Y96C and Q99L mutations.

KRASG12C IN-17, administered orally at a dose of 30 mg/kg once daily for 28 consecutive days, demonstrated significant in vivo efficacy in the SW837 KRAS G12C xenograft model, achieving 103% tumor growth inhibition. Additionally, the same compound, under a 21-day continuous oral administration at 30 mg/kg, resulted in a notable 65.9% tumor reduction in the Ba/F3 KRAS G12C/R68S xenograft model.