Molecule Glue That Stabilizes the LRPPRC-MET-G4 Interaction Complex to Drive MET Downregulation

Targeting the MET oncoprotein is an effective strategy in precision cancer therapy, whereas its clinical efficacy varies dramatically across tumor types. To address this challenge, we explored an alternative approach to downregulate MET expression at transcriptional levels. We identified a cis-regulatory element in the MET proximal promoter region that folds into a stable parallel DNA G-quadruplex (MET-G4). We further determined the high-resolution NMR solution structure of MET-G4 and demonstrated that MET-G4 recruits the cellular LRPPRC protein to promote MET transcription, thereby uncovering a previously unrecognized epigenetic mechanism that drives MET overexpression. Moreover, we characterized the specific G4-binding domain of LRPPRC and elucidated its structural basis for recognition of the MET-G4. Through screening an in-house natural product library, we identified nitidine alkaloid (NIT) as a potent MET-G4 stabilizer. Strikingly, nitidine acts as a molecular glue, strengthening the LRPPRC-MET-G4 interaction and inducing the formation of a stable LRPPRC-NIT-MET-G4 ternary complex. This complex likely alters the structure and function of LRPPRC, ultimately leading to MET downregulation and potent anticancer effects. Notably, this is the first report of a molecular glue that stabilizes a G4-protein complex to silence an oncogene. Additionally, comprehensive in vitro and in vivo experiments demonstrated that nitidine significantly inhibits tumor progression mainly through an LRPPRC-MET-G4-dependent mechanism. Collectively, our study reveals a novel epigenetic regulatory mechanism involving LRPPRC-MET-G4-mediated MET upregulation and suggests a promising therapeutic strategy for MET-driven tumors with molecular glues that target the LRPPRC-MET-G4 interface