Discovery of a Novel and Potent MET Transcription Inhibitor Targeting Promoter G-Quadruplex for the Treatment of NSCLC

c-Met is a promising molecular target in oncological treatment, and related targeted therapy drugs have achieved inspiring results in clinical practice. However, the clinical emergence of acquired resistance to c-Met inhibitors in recent years presents a significant therapeutic challenge. In this study, we identified a novel MET transcriptional inhibitor, C3, which efficiently binds to the G-quadruplex in the MET promoter and suppresses the expression of c-Met. Meanwhile, C3 exhibited potent antitumor activity against nonsmall cell lung cancer (NSCLC) cells and xenograft tumor models. Importantly, as a MET transcription inhibitor, C3 demonstrated superior efficacy compared to conventional c-Met inhibitors in suppressing proliferation in Ba/F3 cell lines, harboring defined c-Met mutations. Thus, C3 could serve as a promising lead for the treatment of NSCLC.