Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519041, Guangdong Province, China.
Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519041, Guangdong Province, China.
Eur J Med Chem. 2022 Jan 5;227:113963. doi: 10.1016/j.ejmech.2021.113963. Epub 2021 Oct 30.
The EGFR family play a significant role in cell signal transduction and their overexpression is implicated in the pathogenesis of numerous human solid cancers. Inhibition of the EGFR-mediated signaling pathways by EGFR inhibitors is a widely used strategy for the treatment of cancers. In most cases, the EGFR inhibitors used in clinic were only effective when the cancer cells harbored specific activating EGFR mutations which appeared to preserve the ligand-dependency of receptor activation but altered the pattern of downstream signaling pathways. Moreover, cancer is a kind of multifactorial disease, and therefore manipulating a single target may result in treatment failure. Although drug combinations for the treatment of cancers proved to be successful, the use of two or more drugs concurrently still was a challenge in clinical therapy owing to various dose-limiting toxicities and drug-drug interactions caused by pharmacokinetic profiles changed. Therefore, a single drug targeting two or multiple targets could serve as an effective strategy for the treatment of cancers. In recent, drugs with diverse pharmacological effects have been shown to be more advantageous than combination therapies due to their lower incidences of side effects and more resilient therapies. Accordingly, dual target-single-agent strategy has become a popular field for cancer treatment, and researchers became more and more interest in the development of novel dual-target drugs in recent years. In this review, we briefly introduce the EGFR family proteins and synergisms between EGFR and other anticancer targets, and summarizes the development of potential dual target inhibitors based on wild-type and/or mutant EGFR for the treatment of solid cancers in the past five years. Additionally, the rational design and SARs of these dual target agents are also presented in detailed, which will lay a significant foundation for the further development of novel EGFR-based dual inhibitors with excellent druggability.
表皮生长因子受体（EGFR）家族在细胞信号转导中发挥重要作用，其过表达与许多人类实体瘤的发病机制有关。通过 EGFR 抑制剂抑制 EGFR 介导的信号通路是治疗癌症的广泛应用策略。在大多数情况下，临床上使用的 EGFR 抑制剂仅在癌细胞具有特定的激活型 EGFR 突变时才有效，这些突变似乎保留了受体激活的配体依赖性，但改变了下游信号通路的模式。此外，癌症是一种多因素疾病，因此单一靶点的操纵可能导致治疗失败。虽然联合用药治疗癌症已被证明是成功的，但由于药代动力学特征改变导致的各种剂量限制毒性和药物相互作用，同时使用两种或更多种药物在临床治疗中仍然是一个挑战。因此，针对两个或多个靶点的单一药物可以作为治疗癌症的有效策略。最近，具有多种药理作用的药物由于副作用发生率较低且治疗更具弹性，已被证明比联合疗法更具优势。因此，双靶标单药策略已成为癌症治疗的热门领域，近年来，研究人员对开发新型双靶标药物越来越感兴趣。在这篇综述中，我们简要介绍了 EGFR 家族蛋白和 EGFR 与其他抗癌靶点之间的协同作用，并总结了过去五年中基于野生型和/或突变型 EGFR 治疗实体瘤的潜在双靶抑制剂的发展情况。此外，还详细介绍了这些双靶药物的合理设计和 SARs，为进一步开发具有良好成药性的新型基于 EGFR 的双抑制剂奠定了重要基础。
