Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

Abnormalactivation of fibroblast growth factor receptors (FGFRs)results in the development and progression of human cancers. FGFR2is frequently amplified or mutated in cancers; therefore, it is anattractive target for tumor therapy. Despite the development of severalpan-FGFR inhibitors, their long-term therapeutic efficacy is hinderedby acquired mutations and low isoform selectivity. Herein, we reportthe discovery of an efficient and selective FGFR2 proteolysis-targetingchimeric molecule, LC-MB12, that incorporates an essential rigid linker.LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2among the four FGFR isoforms; this may promote greater clinical benefits.LC-MB12 exhibits superior potency in FGFR signaling suppression andanti-proliferative activity compared to the parental inhibitor. Furthermore,LC-MB12 is orally bioavailable and shows significant antitumor effectsin FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12is a candidate FGFR2 degrader for alternative FGFR2-targeting strategiesand offers a promising starting point for drug development.