Epidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFR^L858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-9 (EGFR^{Del 19}) and H1975 (EGFR^L858R/T790M) cells, but not that of A549 (EGFR^WT) cells. In addition, 1q could time- and dose-dependently induce degradation of EGFR^L858R/T790M in H1975 cells with a DC₅₀ value of 355.9 nM, while did not show obvious effect on the EGFR^{Del 19} and EGFR^WT protein. Preliminary mechanism study demonstrated that the protein degradation was mediated through ubiquitin-proteasome system (UPS). Furthermore, 1q could significantly induce the apoptosis of H1975 cells and arrest the cells in G₀/G₁ phase. These findings demonstrated that compound 1q could be used as initial lead compound for the development of new EGFR^L858R/T790M degraders based therapy.

表皮生长因子受体 (EGFR) 抑制剂是非小细胞肺癌 (NSCLC) 的一线治疗药物。然而，获得性耐药和副作用的出现在很大程度上阻碍了它们在临床上的应用。新兴技术蛋白水解靶向嵌合体 (PROTAC) 可能是克服这些问题的替代策略。在此，我们报告了基于 CO-1686的 EGFR ^{L858R/T790M降解剂的发现。}有前途的 PROTAC 1q可以有效和选择性地抑制 PC-9 (EGFR ^{Del 19} ) 和 H1975 (EGFR ^L858R/T790M ) 细胞的生长，但不能抑制 A549 (EGFR ^WT ) 细胞的生长。此外，1q可以时间和剂量依赖性地诱导 EGFR 降解^L858R/T790M在H1975细胞中DC ₅₀值为355.9 nM，而对EGFR ^{Del 19}和EGFR ^WT蛋白无明显影响。初步机制研究表明，蛋白质降解是通过泛素-蛋白酶体系统（UPS）介导的。此外，1q可显着诱导H1975细胞凋亡，使细胞停滞于G ₀ /G ₁期。这些发现表明，化合物1q可用作开发新的基于 EGFR ^L858R/T790M降解剂的疗法的初始先导化合物。