Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras,Journal of Medicinal Chemistry

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Exploring Degradation of Mutant and Wild-Type Epidermal Growth Factor Receptors Induced by Proteolysis-Targeting Chimeras
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-08 , DOI: 10.1021/acs.jmedchem.2c00345
Xufen Yu ₁ , Meng Cheng _{2,

3} , Kaylene Lu ₃ , Yudao Shen ₁ , Yue Zhong ₁ , Jing Liu ₁ , Yue Xiong ₃ , Jian Jin ₁

Affiliation

Several epidermal growth factor receptor (EGFR) proteolysis-targeting chimeras (PROTACs), including MS39 and MS154 developed by us, have been reported to effectively degrade the mutant but not the wild-type (WT) EGFR. However, the mechanism underlying the selectivity in degrading the mutant over the WT EGFR has not been elucidated. Here, we report comprehensive structure–activity relationship studies that led to the discovery of two novel EGFR degraders, 31 (MS9449) and 72 (MS9427), and mechanistic studies of these EGFR degraders. Compounds 31 and 72 selectively degraded the mutant but not the WT EGFR through both ubiquitination/proteasome and autophagy/lysosome pathways. Interestingly, we found that the mutant but not the WT EGFR can effectively form EGFR–PROTAC–E3 ligase ternary complexes. Furthermore, we found that PI3K inhibition sensitized WT EGFR to PROTAC-induced degradation and combination treatment with a PI3K inhibitor enhanced antiproliferation activities of EGFR degraders in cancer cells harboring WT EGFR, providing a potential therapeutic strategy for patients with WT EGFR overexpression.

中文翻译：

探索蛋白水解靶向嵌合体诱导的突变型和野生型表皮生长因子受体的降解

据报道，几种表皮生长因子受体 (EGFR) 蛋白水解靶向嵌合体 (PROTAC)，包括我们开发的 MS39 和 MS154，可有效降解突变型 EGFR，但不能降解野生型 (WT) EGFR。然而，相对于 WT EGFR 选择性降解突变体的机制尚未阐明。在这里，我们报告了全面的结构-活性关系研究，这些研究导致了两种新型 EGFR 降解剂31 (MS9449) 和72 (MS9427) 的发现，以及这些 EGFR 降解剂的机制研究。化合物31和72通过泛素化/蛋白酶体和自噬/溶酶体途径选择性降解突变体，但不降解 WT EGFR。有趣的是，我们发现突变体而非WT EGFR可以有效形成EGFR-PROTAC-E3连接酶三元复合物。此外，我们发现PI3K抑制使WT EGFR对PROTAC诱导的降解敏感，并且与PI3K抑制剂联合治疗增强了携带WT EGFR的癌细胞中EGFR降解剂的抗增殖活性，为WT EGFR过表达的患者提供了潜在的治疗策略。

更新日期：2022-06-08

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