Molecular 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. Herein, we explore an alternative approach to downregulate MET at the transcriptional level. We identify a cis-regulatory element in the MET proximal promoter that forms a stable parallel G-quadruplex (MET-G4). We determine the high-resolution NMR solution structure of this MET-G4 and demonstrate that MET-G4 recruits LRPPRC to promote MET transcription, uncovering a previously unrecognized epigenetic mechanism that drives MET overexpression. We further characterize LRPPRC's G4-binding domain and its structural basis for MET-G4 recognition. Through screening an in-house natural product library, we identify nitidine (NIT) as a MET-G4 stabilizer that 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, thereby downregulating MET expression and exerting the well-known anticancer effects of nitidine. Moreover, comprehensive in vitro and in vivo experiments demonstrate that nitidine significantly inhibits tumor progression through an LRPPRC-MET-G4-dependent mechanism. Collectively, our study suggests an epigenetic regulatory mechanism involving LRPPRC-MET-G4-mediated MET upregulation and provides a promising therapeutic strategy for MET-driven tumors using molecular glues that target the LRPPRC-MET-G4 interface.