Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
J Med Chem. 2022 Jun 23;65(12):8416-8443. doi: 10.1021/acs.jmedchem.2c00345. Epub 2022 Jun 8.
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, (MS9449) and (MS9427), and mechanistic studies of these EGFR degraders. Compounds and 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.
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，已被报道可有效降解突变型但不降解野生型（WT）EGFR。然而，导致突变型 EGFR 选择性降解而不降解 WT EGFR 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，该研究导致发现了两种新型的 EGFR 降解剂， （MS9449）和 （MS9427），并对这些 EGFR 降解剂进行了机制研究。化合物 和 通过泛素化/蛋白酶体和自噬/溶酶体途径选择性地降解突变型但不降解 WT EGFR。有趣的是，我们发现突变型但不是 WT EGFR 可以有效地形成 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 抑制剂联合治疗可增强 WT EGFR 过表达的癌细胞中 EGFR 降解剂的抗增殖活性，为 WT EGFR 过表达的患者提供了一种潜在的治疗策略。
