<br>发现能够降解多种 EGFR 突变蛋白的新型 EGFR-PROTAC,European Journal of Medicinal Chemistry

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发现能够降解多种 EGFR 突变蛋白的新型 EGFR-PROTAC
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-05-16 , DOI: 10.1016/j.ejmech.2024.116489
Yu Du ₁ , Shi Shi ₂ , Chen Shu ₁ , Yezi He ₃ , Wangyang Xu ₃ , Daochen Wu ₃ , Yushu Tian ₃ , Mingyang Kong ₃ , Jiahuan He ₃ , Wenhui Xie ₃ , Yijia Qiu ₃ , Yungen Xu ₁ , Yi Zou ₃ , Qihua Zhu ₁

Affiliation

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），但其临床应用仍然很大程度上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) 技术有潜力通过新颖的作用机制克服突变型 EGFR 的获得性耐药。在这项研究中，我们通过先导化合物的结构修饰开发了候选降解剂，该降解剂对 HCC-827 细胞表现出有限的抗增殖活性。与化合物相比，对 HCC-827 细胞、NCI–H1975 细胞和 NCI–H1975-TM 细胞表现出显着的抗增殖活性（IC50 分别为 0.009 μM、0.49 μM 和 3.24 μM），并显着诱导降解这些细胞系中的 EGFR 蛋白（DC 分别为 17.93 nM、0.25 μM 和 0.63 μM）。进一步的研究证实，通过降解突变型 EGFR 蛋白，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，对表达野生型 EGFR 的 A431 和 A549 细胞没有显示出抑制活性，从而消除了野生型 EGFR 抑制带来的潜在毒副作用。总体而言，我们的研究为 EGFR-PROTAC 作为针对 EGFR 获得性突变的潜在治疗策略提供了有前景的见解。

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Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins

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 by structural modifications of the lead compound , which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound , exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI–H1975 cells, and NCI–H1975-TM cells (IC = 0.009 μM, 0.49 μM and 3.24 μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC = 17.93 nM, 0.25 μM and 0.63 μM, respectively). Further investigations confirmed that exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, 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.

更新日期：2024-05-16

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