Abstract：
Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC50 = 0.009 μM, 0.49 μM and 3.24 μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 μM and 0.63 μM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.
摘要：
尽管三代表皮生长因子受体（EGFR）-TK抑制剂已被批准用于治疗非小细胞肺癌（NSCLC），它们的临床应用在很大程度上仍然受到获得性耐药介导的新EGFR突变和副作用的阻碍。蛋白水解靶向嵌合体（PROTAC）技术具有通过新的作用机制克服突变EGFR的获得性抗性的潜力。在这项研究中,我们通过先导化合物13的结构修饰开发了候选降解剂IV-3,其对HCC-827细胞表现出有限的抗增殖活性.与化合物13相比，IV-3对HCC-827细胞具有显著的抗增殖活性，NCI-H1975细胞,和NCI-H1975-TM细胞(IC50=0.009μM，0.49μM和3.24μM，分别)，以及显着诱导这些细胞系中EGFR蛋白的降解（DC50=17.93nM，0.25μM和0.63μM，分别)。进一步的研究证实，通过突变EGFR蛋白的降解，IV-3在所有异种移植肿瘤模型中表现出优异的抗肿瘤活性。此外，IV-3对表达野生型EGFR的A431和A549细胞无抑制活性。从而消除了野生型EGFR抑制产生的潜在毒副作用。总的来说,我们的研究为EGFR-PROTACs作为EGFR获得性突变的潜在治疗策略提供了有希望的见解.
