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 molecule, 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 clinical 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.
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