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- W4377693783 abstract "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." @default.
- W4377693783 created "2023-05-24" @default.
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- W4377693783 date "2023-05-23" @default.
- W4377693783 modified "2023-10-01" @default.
- W4377693783 title "Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer" @default.
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- W4377693783 doi "https://doi.org/10.1021/acs.jmedchem.3c00150" @default.
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