Currently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development. Therefore, we designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders. Among them, 13a and 13b significantly inhibited NCI–H1975 cells proliferation with IC₅₀ values of 58.08 nM and 46.82 nM, respectively, whereas exhibited more than 100 μM against A549 or H1299 cells, whose selectivity was more than 1700-fold. 13a and 13b potently induced the EGFR^L858R/T790M degradation by ubiquitin proteasome system in a time- and dose-dependent manner but not that of EGFR^WT, and the DC₅₀ values of 13b was 13.2 nM, which was the most potent compound in current known CRBN-recruiting EGFR^L858R/T790M degraders. 13a and 13b dramatically induced cell apoptosis, cell cycle arrest and inhibited downstream signaling pathways. Furthermore, 13a and 13b effectively and selectively inhibited NCI–H1975 xenograft tumor growth with good pharmacokinetics (PK) properties in vivo. These findings demonstrate that 13a and 13b could serve as candidates for developing the drug for treating NSCLC.

目前，表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）广泛用于治疗非小细胞肺癌（NSCLC）。然而，不可避免的耐药性和副作用是目前推动新疗法的主要障碍。蛋白水解靶向嵌合体 (PROTAC) 是一种最近开发的靶向蛋白质进行降解的技术，已被用于药物开发。因此，我们设计、合成和评估了一系列 CRBN 招募 EGFR 降解剂。其中，13a和13b显着抑制 NCI-H1975 细胞增殖，IC ₅₀值分别为 58.08 nM 和 46.82 nM，而对 A549 或 H1299 细胞的抑制作用超过 100 μM，其选择性超过 1700 倍。13a和13b以时间和剂量依赖性方式有效诱导泛素蛋白酶体系统降解EGFR ^{L858R/T790M ，而不是EGFR WT ，} 13b的DC ₅₀值为13.2 nM，是目前最有效的化合物已知 CRBN 招募 EGFR ^L858R/T790M降解剂。图13a和13b显着诱导细胞凋亡、细胞周期停滞并抑制下游信号通路。此外，13a和13b有效且选择性地抑制 NCI-H1975 异种移植肿瘤生长，具有良好的体内药代动力学 (PK) 特性. 这些发现表明，13a和13b可以作为开发治疗 NSCLC 药物的候选者。