Design, synthesis, and evaluation of 4(1H)-quinolinone and urea derivatives as KRASG12C inhibitors with potent antitumor activity against KRAS-mutant non-small cell lung cancer

Abstract

KRAS^G12C is the most prevalent KRAS mutation in non-small cell lung cancer (NSCLC) and has emerged as a promising therapeutic target. Herein, two series of novel 4(1H)-quinolinone and urea compounds were designed based on the reported KRAS^G12C inhibitor SH-9. Many compounds showed significantly growth inhibitory activity against human NSCLC cells with KRAS^G12C mutation in cell viability assays. Compound 20a exhibited an IC₅₀ value of 0.5 μM in KRAS^G12C-mutant NCI-H358 cells with 21-fold selectivity over KRAS^WT NCI-H2228 cells. LC-MS analysis indicated that compounds 14c, 14h and 20a covalently bound to KRAS^G12C rather than KRAS^WT. Moreover, these compounds could remarkably trap KRAS^G12C in its inactive state by blocking SOS1-mediated GDP/GTP exchange. Furthermore, treatment of NCI-H358 but not NCI-H2228 cells with 20a dose-dependently reduced the phosphorylation of KRAS downstream effectors ERK and AKT. Importantly, 20a significantly inhibited tumor growth in NCI-H358 xenograft models by suppressing KRAS^G12C signalling. These results indicate that 20a is a promising candidate worthy of further investigation.

Keywords: 4(1H)-quinolinone; Covalent inhibitor; KRAS(G12C) mutation; Non-small cell lung cancer; Urea.