Discovery of a tribenzophenazine analog for binding to the KRAS mRNA G-quadruplex structures in the cisplatin-resistant non-small cell lung cancer.

Lung cancer is the malignant tumor with the highest morbidity and mortality rate worldwide, of which non-small cell lung cancer (NSCLC) accounts for approximately 85%. KRAS mutations are one of the significant mechanisms underlying the occurrence, development, immune escape, and chemotherapy resistance of NSCLC. Two KRAS inhibitors are approved by FDA for the treatment of NSCLC in the past three years. However, they are only effective to KRAS G12C mutant, and moreover, innate and acquired drug resistance is already reported, leaving an urgent need to block KRAS pathways through novel targets. In this study, we focused on the discovery of ligands targeting the RNA G-quadruplexes (RG4s) in 5'-untranslated region (5'-UTR) of KRAS mRNA, and a novel tribenzophenazine analog (MBD) was identified as the lead compound. Further mechanisms were discussed in A549/DDP cells, a cisplatin-resistant and KRAS-mutant NSCLC cell line. Antitumor efficacy was verified both in vitro in A549/DDP cells, and in vivo in a nude mouse xenograft model implanted with A549/DDP cells. To sum up, our results suggest the potential of MBD as a prominent anti-KRAS-driven NSCLC agent, and propose a new idea for the development of small molecule ligands targeting KRAS RG4s.