EGFR耐药突变及其小分子抑制剂研究进展 <sup>*</sup>

doi:10.13523/j.cb.20191012

中国生物工程杂志

2019, Vol. 39

Issue (10): 97-104 DOI: 10.13523/j.cb.20191012

综述

EGFR耐药突变及其小分子抑制剂研究进展 ^*

李文¹,陈洁¹,胡伟男¹,漆亚云¹,付毅红¹,刘佳敏¹,王贞超^1,^2,^3,^**(

),欧阳贵平^1,^3,^4,^**(

)

1 贵州大学药学院贵阳 550025
2 贵州医科大学药用植物功效与利用国家重点实验室贵阳 550014
3 贵州省合成药物工程实验室贵阳 550025
4 贵州大学精细化工研究开发中心贵阳 550025

Research Advances in the Study of EGFR Mutations Resistance and Its Small Molecule Inhibitors

LI Wen¹,CHEN Jie¹,HU Wei-nan¹,QI Ya-yun¹,FU Yi-hong¹,LIU Jia-min¹,WANG Zhen-chao^1,^2,^3,^**(

),OUYANG Gui-ping^1,^3,^4,^**(

)

1 College of Pharmacy, Guizhou University, Guiyang 550025, China
2 State Key Laboratory of Efficacy and Utilization of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
3 Center for Research of Fine Chemicals, Guizhou University, Guiyang 550025, China
4 Center for Research of Fine Chemicals, Guizhou University, Guiyang 550025, China

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摘要：

表皮生长因子受体(epidermal growth factor receptor, EGFR)是一种具有酪氨酸激酶活性的重要跨膜受体,在多种恶性肿瘤中异常表达,与肿瘤细胞增殖、分化、转移等生命活动密切相关。EGFR已成为治疗肿瘤的靶点,针对该靶点设计的药物主要分为单克隆抗体和小分子抑制剂两大类,小分子抑制剂易导致EGFR出现突变而产生耐药现象,从而影响其临床应用。突变主要发生在酪氨酸激酶区域ATP结合位点附近,主要为19号外显子上的缺失突变,18号和21号外显子上的点突变。针对近几十年来国内外研究者对EGFR出现的耐药突变类型,及其与小分子抑制剂的相互作用方式进行综述,以期为后续EGFR靶点药物的研发提供参考。

关键词： 表皮生长因子受体; EGFR小分子抑制剂; 耐药; 作用方式

Abstract:

Epidermal growth factor receptor (EGFR) is an important transmembrane receptor with tyrosine kinase activity, which is abnormally expressed in a variety of malignant tumors and closely related to the proliferation, differentiation, metastasis and other life activities of tumor cells. At present, EGFR has been considered as a target for the treatment of tumors, and the drugs targeting on EGFR are mainly divided into two categories, one is monoclonal antibody drugs, and the other is small molecular kinase inhibitors. Small molecule inhibitors are prone to lead to EGFR mutation and drug resistance, thus affecting their clinical application. These mutations occur mainly near the ATP-binding site of the tyrosine kinase region, which are mainly deletion mutations on exon 19 and point mutations on exons 18 and 21.The types of drug-resistant mutations of EGFR and the ways in which they interact with small molecule inhibitors have been reviewed, with a view to providing references for the subsequent research and development of EGFR targeted drugs.

Key words: EGFR EGFR small molecule inhibitors Resistance Interaction

收稿日期: 2019-03-02 出版日期: 2019-11-12

ZTFLH:

Q814

基金资助: * 药用植物功效与利用国家重点实验室(FAMP201707K);国家自然科学基金(21867004);贵州省科技计划项目(黔科合基础[2018]1051)

通讯作者: 王贞超,欧阳贵平 E-mail: wzc.4884@163.com;oygp710@163.com

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引用本文:

李文,陈洁,胡伟男,漆亚云,付毅红,刘佳敏,王贞超,欧阳贵平. EGFR耐药突变及其小分子抑制剂研究进展 ^*[J]. 中国生物工程杂志, 2019, 39(10): 97-104.

LI Wen,CHEN Jie,HU Wei-nan,QI Ya-yun,FU Yi-hong,LIU Jia-min,WANG Zhen-chao,OUYANG Gui-ping. Research Advances in the Study of EGFR Mutations Resistance and Its Small Molecule Inhibitors. China Biotechnology, 2019, 39(10): 97-104.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20191012 或 https://manu60.magtech.com.cn/biotech/CN/Y2019/V39/I10/97

图1 EGFR的外显子结构和酪氨酸激酶结构域内的突变[22]

图2 吉非替尼结构与EGFR-吉非替尼复合晶体结构[26]

表1 EGFR小分子抑制剂研究近况

图3 厄洛替尼结构与EGFR-厄洛替尼复合晶体结构[27]

图4 阿法替尼结构与EGFR-阿法替尼复合晶体结构

图5 奥希替尼结构与EGFR-奥希替尼复合晶体结构[32]

图6 WZ4002结构与EGFR-WZ4002复合晶体结构[34]

图7 艾维替尼结构与EGFR-艾维替尼复合晶体结构[35]

图8 EAI045结构与EGFR-EAI045复合晶体结构[36]

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