Zhang Die, Zhao Jumei, Yang Yue, Dai Qiangfang, Zhang Ning, Mi Zhikuan, Hu Qianqian, Liu Xiaolong
School of Medicine, Yan'an University, Yan'an City, China.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2481392. doi: 10.1080/14756366.2025.2481392. Epub 2025 Apr 2.
Overactivation of the epidermal growth factor receptor (EGFR) is prevalent in various tumours, rendering it a promising target for cancer therapy, particularly in the treatment of non-small cell lung cancer (NSCLC). Although the first through third generations of EGFR tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy, the emergence of drug resistance continues to pose a challenge. Current research is now focused on fourth-generation EGFR-TKIs, which specifically target the EGFR harbouring the C797S mutation. This review examines the design strategies, antitumor activity both and , binding modes, pharmacokinetics, as well as the advantages and disadvantages of each inhibitor, alongside the progress of clinical stage research related to fourth-generation inhibitors. Additionally, the review discusses future development directions for fourth-generation EGFR-TKIs, aiming to provide insights for successful research and development in this field.
表皮生长因子受体（EGFR）的过度激活在各种肿瘤中普遍存在，使其成为癌症治疗的一个有前景的靶点，特别是在非小细胞肺癌（NSCLC）的治疗中。尽管第一代至第三代EGFR酪氨酸激酶抑制剂（TKIs）已显示出显著疗效，但耐药性的出现仍然构成挑战。目前的研究集中在第四代EGFR-TKIs，其特异性靶向携带C797S突变的EGFR。本综述研究了各抑制剂的设计策略、抗肿瘤活性、结合模式、药代动力学，以及优缺点，同时探讨了与第四代抑制剂相关的临床阶段研究进展。此外，本综述还讨论了第四代EGFR-TKIs的未来发展方向，旨在为该领域的成功研发提供见解。
