Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China.
Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China.
Bioorg Chem. 2022 Nov;128:106057. doi: 10.1016/j.bioorg.2022.106057. Epub 2022 Aug 1.
The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have accomplished impressive clinical achievements in the treatment of non-small-cell lung cancer (NSCLC). Nonetheless, the acquired drug resistance largely limits their clinical use. The tertiary C797S mutation in the kinase domain of EGFR is one of the major mechanisms responsible for the drug resistance. Therefore, much attention has been focused on the development of the fourth-generation EGFR-TKIs to target triple mutant epidermal growth factor receptor (EGFR) with C797S mutation. In this review, we outline the panorama of the fourth-generation EGFR-TKIs reported up to now with the attention paid on the design strategy, binding mode and antitumor activity of these EGFR-TKIs. We also discuss the challenges and prospects of the fourth-generation EGFR-TKIs.
第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）在治疗非小细胞肺癌（NSCLC）方面取得了令人瞩目的临床成就。然而，获得性耐药性在很大程度上限制了它们的临床应用。EGFR 激酶结构域中的三级 C797S 突变是导致耐药性的主要机制之一。因此，人们高度关注开发第四代 EGFR-TKIs，以针对具有 C797S 突变的三突变表皮生长因子受体（EGFR）。在这篇综述中，我们概述了迄今为止报道的第四代 EGFR-TKIs 的全景，重点介绍了这些 EGFR-TKIs 的设计策略、结合模式和抗肿瘤活性。我们还讨论了第四代 EGFR-TKIs 的挑战和前景。
