EGFR靶向抗肿瘤抑制剂的研究进展_开题报告

摘要

目的　介绍小分子EGFR酪氨酸激酶抑制剂的研究进展,为其深入研究提供参考。

方法　查阅、总结近几年国内、外有关文献。

结果与结论　靶向酪氨酸激酶的小分子抑制剂研究有了长足进展。随着小分子酪氨酸激酶抑制剂的作用机制及构效关系研究的不断深入,为该类抑制剂的合理药物设计提供可能,评价更加成熟,在抗肿瘤领域有较为广阔的应用前景。

关键词EGFR酪氨酸激酶抑制剂；受体酪氨酸激酶；ERBB的激活；ERBB抑制剂的分类及进展；抗肿瘤作用

《EGFR靶向抗肿瘤抑制剂的研究进展》开题报告

文献综述

在过去的几十年中，对癌症发生及发展基本原则的理解已经取得了革命性的进展，对分子异常在癌症中的重要作用有了更深的认识，这些发现导致了靶向分药物的发展。其中一个靶点就是表皮生长因子受体（EGFR）, 它是一个在癌症细胞中失调的跨膜蛋白，与恶性肿瘤的发生发展和侵袭有很大的关系[1, 2]。抑制EGFR的信号已经被认为是一种控制肿瘤增殖的有效策略，近几十年对其活性的广泛研究，终于促使了吉非替尼和厄洛替尼获得美国FDA批准。然而，耐药现象的迅速出现以及带有EGFR突变的病患对于酪氨酸激酶抑制剂（TKI）的获得性耐药使得药物延缓疾病发展的平均时间降低至只有数个月。因此逆转EGFR TKIs 耐药成为当今世界研究的热点。

EGFR是原癌基因c-erbB1的表达产物，是表皮生长因子受体（HER）家族成员之一。Epidermal Growth Factor Receptor; EGFR）是上皮生长因子（EGF）细胞增殖和信号传导的受体。EGFR属于ErbB受体家族的一种，该家族包括EGFR (ErbB-1), HER2/c-neu(ErbB-2), Her 3(ErbB-3) 和 Her 4(ErbB-4)。EGFR也被称作HER1、ErbB1，突变或过表达一般会引发肿瘤。EGFR是一种糖蛋白，属于酪氨酸激酶型受体，细胞膜贯通，分子量170Da。HER家族在细胞生理过程中发挥重要的调节作用。EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面，EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用。EGFR分为三区:胞外配体结合区，跨膜区和胞内激酶区。EGFR等蛋白酪氨酸激酶功能缺失或其相关信号通路中关键因子的活性或细胞定位异常，均会引起肿瘤、糖尿病、免疫缺陷及心血管疾病的发生。

人类EGFR家族由4个独特而结构相似的酪氨酸激酶受体组成,分别是:c2ErbB1/EGFR/EGFR1(epidermalgrowthfac2torreceptor,EGFR),c2ErbB2/HER2(

通常指HER2),c2ErbB3/HER3和c2ErbB4/HER4。它们通过将ATP的γ磷酸基转移到功能蛋白的酪氨酸残基上,引发下游生物反应级联,参与激活一系列复杂的细胞信号转导途径,从而调控诸如有丝分裂、细胞周期进程和分化等多种细胞功能,与多种恶性肿瘤的发生、发展及预后等密切相关。近年来,RTKs(receptortyrosinekinases)

受体为靶点的抗肿瘤研究成为了肿瘤治疗研究中的热点领域,主要包括两个方面:一是以其胞内、胞外结构为靶点制造抗体,通过配体介导的细胞免疫毒性杀灭肿瘤细胞,包括单克隆抗体、双特异性抗体、单链Fv抗体、免疫毒素共轭物,另一个是设计小分子ATP或底物类似物,通过与ATP或底物竞争性结合胞外的配体结合位点,阻断分子内酪氨酸的自身磷酸化,阻断酪氨酸激酶活化,抑制EGFR激活,阻止下游信号转导,从而抑制细胞周期进程、加速细胞凋亡、抑制血管生成、抑制浸润和转移。

二、^范文提纲

1、EGFR的概述

1.1 EGFR的简介

1.2EGFR的分布

1.3 EGFR抑制剂的研究进展

  1.4 EGFR抑制剂的分类

    1.4.1单克隆抗体

  1.5 EGFR抑制剂的耐药机制

1.5.1 原发耐药

1.5.2 获得性耐药

EGFR家族RTKS结构与肿瘤的关系

2.1RTKS的简介

2.2RTKS的结构及分类

2.3RTKS与肿瘤的关系

EGFR家族与ERBB抑制剂的研究进展

3.1ERBB的简介

3.2ERBB的激活

3.3ERBB抑制剂的分类

  3.4 ERBB抑制剂抗肿瘤作用的比较

3.5 ERBB抑制剂的研究进展

参考文献

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