EGFR变构抑制剂在小细胞肺癌治疗中的作用和未来发展  

The Role and Future Development of EGFR Allosteric Inhibitors in the Treatment of Small Cell Lung Cancer

作　　者：贾硕磊 周庆发 

机构地区：[1]中国药科大学理学院,江苏 南京

出　　处：《药物化学》2024年第3期185-195,共11页Hans Journal of Medicinal Chemistry

摘　　要：表皮生长因子受体(EGFR)过表达和突变与非小细胞肺癌的发生密切相关。EGFR激活突变作为非小细胞肺癌的致癌因素,EGFR小分子抑制剂的开发也不断在进行。然而从2016年首次报道EGFRC797S突变成为第三代不可逆抑制剂的主要耐药机制以来,至今仍未有对抗EGFRC797S三级突变特效药获得审批。因此,开发第四代EGFR抑制剂具有重要意义。本文综述了EGFR继发性突变的过程以及EGFR变构抑制剂的最新药物化学进展。我们希望这些数据能启发读者新的想法,开发出对EGFRC797S突变有效的新型第四代EGFR变构抑制剂。Epidermal growth factor receptor (EGFR) overexpression and mutations are closely associated with the development of non-small cell lung cancer. EGFR-activating mutations function as oncogenic drivers in non-small cell lung cancer, driving ongoing efforts in the development of small-molecule inhibitors targeting EGFR. However, since the identification of the EGFRC797S mutation in 2016 as the primary resistance mechanism for third-generation irreversible inhibitors, no potent drug targeting the EGFRC797S tertiary mutation has been approved. Consequently, the development of fourth-generation EGFR inhibitors is of paramount importance. In this article, we provide a comprehensive overview of the process of acquired EGFR mutations and recent advancements in medicinal chemistry related to acquired-resistant fourth-generation EGFR small-molecule inhibitors, with a particular focus on allosteric and reversible inhibitors designed to counteract the EGFRC797S mutation. We aim for these insights to inspire readers with innovative approaches in developing novel fourth-generation EGFR small-molecule inhibitors that effectively combat the EGFRC797S mutation.

关 键 词：EGFR抑制剂 变构抑制剂 非小细胞肺癌 

分 类 号：R73[医药卫生—肿瘤]