Converting FGFR inhibitors into selective covalent molecular glue degraders via transposable gluing handles

Molecular glue degraders (MGDs) have emerged as a transformative therapeutic modality, offering the potential to deplete undruggable or pathogenic proteins. However, the rational design of MGDs remains inherently challenging compared to traditional heterobifunctional degraders. Recently, the implementation of transposable chemical gluing handles has provided an efficient approach to convert established protein-targeting ligands into target-specific MGDs. In this study, by incorporating diverse molecular glue handles and amino acid-based degrons into the solvent-exposed exit vectors of infigratinib, we synthesized a library of 30 candidate MGDs. Preliminary screening and subsequent lead optimization identified LC-MG-5 and LC-MG-10 as highly efficient degraders of FGFR2. In cellular models, both compounds demonstrated potent suppression of FGFR2-mediated signaling pathways. Mechanistic investigations revealed that the covalent engagement of the gluing handle is a critical determinant for successful proteasomal degradation of FGFR2. This work provides a framework for the rational transformation of kinase inhibitors into covalent molecular glue degraders, underscoring the potential of FGFR degradation as a next-generation precision medicine strategy for FGFR2-driven malignancies.

Fibroblast growth factor receptor 2; Gastric cancer; Molecular glue; Targeted protein degradation.