用于临床治疗非小细胞肺癌的 EGFR 抑制剂的研究进展  

Research progress in EGFR-TKIs for clinical treatment of NSCLC

作　　者：毛龙飞 吴琼[1] 孙格 李月明 MAO Long-fei;WU Qiong;SUN Ge;LI Yue-ming(State Key Laboratory of Medicinal Chemical Biology,College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research,Nankai University,Tianjin 300353,China;School of Chemistry and Chemical Engineering,Henan Normal University,Xinxiang 453001.China;School of Basic Medical Sciences,Southern Medical University,Guangzhou 510515,China)

机构地区：[1]南开大学药学院/药物化学生物学国家重点实验室/天津市分子药物研究重点实验室,天津300353 [2]河南师范大学化学化工学院,河南新乡453007 [3]南方医科大学基础医学院,广东广州510515

出　　处：《中国药物化学杂志》2021年第2期152-161,共10页Chinese Journal of Medicinal Chemistry

基　　金：天津市研究生科研创新项目(2019YJSB077);2019年度河南省重点科技攻关项目(192102310142)。

摘　　要：世界癌症研究机构(IARC)调查结果显示,肺癌是发生率和死亡率最高的癌症,其中又以非小细胞肺癌所占比例最高(约80%)。小分子药物抑制表皮生长因子受体-酪氨酸激酶可实现靶向治疗,因其高效、低毒、高选择性等优势在非小细胞肺癌的治疗中占有非常重要的地位。上世纪八十年代,第一代可逆、非选择性的具有喹啉胺结构的表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKIs)吉非替尼和厄洛替尼问世,与传统的化学治疗药物相比,此类抑制剂显著延缓了疾病的进展,但服药后出现的耐药性一直是其短板。针对这一问题,后续开发了基于喹啉胺结构的不可逆、非选择性的第二代EGFR-TKIs,具有嘧啶结构的不可逆的、选择性抑制突变的第三代EGFR-TKIs以及目前正在研发的第四代具有大环结构的EGFR-TKIs。本文概述了当前临床使用的EGFR-TKI类抗非小细胞肺癌药物及其与相应的靶蛋白之间的作用方式,希望能为非小细胞肺癌临床治疗及同类药物的设计提供参考。Census by The International Agency for Research on Cancer(IARC) shows that lung cancer is the leading cause of cancer incidence and mortality,among which non-small cell lung cancer(NSCLC) owns the highest proportion(about 80%).Targeted therapy using small molecule inhibitors against epidermal growth factor receptor-tyrosine kinase has shown the advantage of high efficiency,high selectivity and low toxicity in the treatment of NSCLC.In the 1980′s,the first generation of EGFR tyrosine kinase inhibitors(EGFR-TKIs) with quinoline amine structure were developed.These EGFR-TKIs were reversible and non-selective EGFR-TKIs,and significantly delayed the progress of the disease compared with traditional chemotherapy.However,these therapeutics also showed their weakness of EGFR-TKIs such as drug resistance or adverse effects.To tackle this problem,the second generation of irreversible,nonselective EGFR-TKIs bearing the quinoline amine structure,the third generation of irreversible,selective inhibitors bearing the pyrimidine structure,and the fourth generation EGFR-TKIs bearing the macrocyclic structures were developed for the treatment of NSCLC.In this paper,the clinically used EGFR-TKI-type anti-NSCLC drugs were reviewed,and their possible interaction with the target-proteins was discussed to provide information for the clinical treatment of NSCLC as well as the design of similar anti-NSCLC drugs.

关 键 词：癌症 非小细胞肺癌 表皮生长因子受体-酪氨酸激酶 靶向治疗 耐药性 

分 类 号：R914[医药卫生—药物化学]