The growing concern about drug resistance to KRAS G12C inhibitors emphasizes the urgent need for effective therapies targeting NSCLC with KRAS G12C mutation. In this research, a series of quinazoline-based stilbene derivatives were designed, synthesized and assayed for cytotoxic activities against human KRAS G12C mutant NSCLC NCI-H358 cells. Among them, K882 (4e) exhibited remarkable inhibitory activities on tumor cell proliferation, migration and invasion, as well as tumor organoids growth in vitro. Subsequent study revealed that K882 arrested NCI-H358 cell cycle in G2/M phase and induced apoptosis. In a NCI-H358 xenograft tumor model, K882 showed potential tumor inhibition effect in vivo without causing obvious organ damage. Mechanistically, K882 bound to ATP binding hydrophobic pocket of Src and inhibited its downstream signaling pathways including Jak/Stat, PI3K/Akt and RAS/MAPK activation, thereby exerting its anti-tumor effect. These findings highlight the promising potential of K882 as a therapeutic targeting agent for the treatment of KRAS mutant NSCLC while also providing novel insights into targeted therapy strategies for this type of malignancy. Furthermore, the information of structure-activity relationship presents valuable molecular design blueprints for the development of novel and highly potent compounds targeting Src.
