LC-MB11

Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of human cancers.FGFR2 is frequently amplified or mutated in cancers; therefore, it is an attractive target for tumor therapy.Despite the development of several pan-FGFR inhibitors, their long-term therapeutic efficacy is hindered by acquired mutations and low isoform selectivity.Herein, we report the discovery of an efficient and selective FGFR2 proteolysis-targeting chimeric mol., LC-MB12, that incorporates an essential rigid linker.LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2 among the four FGFR isoforms; this may promote greater clin. benefits.LC-MB12 exhibits superior potency in FGFR signaling suppression and anti-proliferative activity compared to the parental inhibitor.Furthermore, LC-MB12 is orally bioavailable and shows significant antitumor effects in FGFR2-dependent gastric cancer in vivo.Taken together, LC-MB12 is a candidate FGFR2 degrader for alternative FGFR2-targeting strategies and offers a promising starting point for drug development.