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.

中文翻译：

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发现一种选择性口服生物可利用的 FGFR2 降解剂用于治疗胃癌

成纤维细胞生长因子受体（FGFR）的异常激活导致人类癌症的发生和进展。FGFR2 在癌症中经常被扩增或突变；因此，它是肿瘤治疗的一个有吸引力的靶点。尽管开发了几种泛 FGFR 抑制剂，但它们的长期治疗效果受到获得性突变和低亚型选择性的阻碍。在此，我们报告发现了一种高效、选择性的 FGFR2 蛋白水解靶向嵌合分子 LC-MB12，它包含一个必需的刚性接头。LC-MB12 优先内化并降解四种 FGFR 亚型中膜结合的 FGFR2；这可能会带来更大的临床效益。与亲代抑制剂相比，LC-MB12 在 FGFR 信号传导抑制和抗增殖活性方面表现出卓越的效力。此外，LC-MB12 具有口服生物利用度，并且在体内对 FGFR2 依赖性胃癌具有显着的抗肿瘤作用。综上所述，LC-MB12 是替代 FGFR2 靶向策略的候选 FGFR2 降解剂，并为药物开发提供了一个有希望的起点。