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

• Published in: Journal of medicinal chemistry 2023-06, Vol.66 (11), p.7438-7453
• Main Authors: Ma, Lin, Li, Yingying, Luo, Ruixiang, Wang, Yuhan, Cao, Jiaqi, Fu, Weitao, Qian, Bolan, Zheng, Lei, Tang, Longguang, Lv, Xinting, Zheng, Lulu, Liang, Guang, Chen, Lingfeng
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Humans; Mutation; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Receptor, Fibroblast Growth Factor, Type 2; Signal Transduction; Stomach Neoplasms - pathology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00150

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.