Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed and approved by Food and Drug Administration for the treatment of non-small-cell lung cancers, but their efficacy can be compromised by acquired drug resistance conferred by EGFR-mutant variants. Here, we described the discovery of a novel E3 ligase von Hippel-Lindau-recruiting EGFR degrader, MS39 (compound 6), and a first-in-class E3 ligase cereblon-recruiting EGFR degrader, MS154 (compound 10), using the proteolysis targeting chimera technology. These compounds potently induced the degradation of mutant but not wild-type EGFR in an E3 ligase-dependent manner in cancer cell lines and effectively suppressed the growth of lung cancer cells compared with the corresponding negative controls. The global proteomic analyses revealed that the compounds were highly selective for EGFR. Furthermore, both compounds were bioavailable in mouse pharmacokinetic studies, and compound 6 is the first EGFR degrader suitable for in vivo efficacy studies. Overall, we provide a set of well-characterized chemical tools to the research community.

中文翻译：

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发现有效的选择性表皮生长因子受体（EGFR）双功能小分子降解物。

几种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂已被开发并获得食品药品监督管理局的批准，可用于治疗非小细胞肺癌，但EGFR突变体赋予的获得性耐药性可能会削弱它们的功效。在这里，我们描述了使用蛋白水解技术发现新型E3连接酶von Hippel-Lindau募集的EGFR降解物MS39（化合物6）和同类中首个E3连接酶大脑再生的EGFR降解剂MS154（化合物10）。针对嵌合体技术。与相应的阴性对照相比，这些化合物以E3连接酶依赖性方式有效诱导突变体而不是野生型EGFR的降解，并有效抑制了肺癌细胞的生长。全球蛋白质组学分析表明，这些化合物对EGFR具有高度选择性。此外，这两种化合物在小鼠药代动力学研究中均具有生物利用度，并且化合物6是首个适用于体内功效研究的EGFR降解剂。总体而言，我们为研究社区提供了一套功能完备的化学工具。