EGFR选择性抑制剂的筛选与评价
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- 英文论文题名：The screening and evaluation of EGFR selective inhibitors
- 论文作者：童依 ; 郝永佳 ; 朱丽丽 ; 李洪林
- 英文论文作者：Yi Tong ; Yongjia Hao ; Lili Zhu ; Honglin Li ; School of Pharmacy ; East China University of Science and Technology
- 年：2016
- 作者机构：华东理工大学药学院;
- 论文关键词：表皮生长因子受体 ; 耐药 ; 选择性抑制剂
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十五分会：化学信息学与化学计量学
- 语种：中文
- 分类号：TQ460.1
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十五分会 ; 化学信息学与化学计量学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：111k
- 原文格式：D
- 会议级别：全国
摘要
表皮生长因子受体(EGFR)是一种受体型酪氨酸激酶,其异常活化和过表达导致肿瘤的发生和发展,因此靶向EGFR小分子抑制剂成为肿瘤治疗的重要策略之一。以吉非替尼和厄洛替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)在治疗非小细胞肺癌中发挥重要作用,但多数患者用药一段时间后对此类药物产生耐药性~([1,2]),因此本课题组致力开发高活性、高选择性的新型EGFR突变体小分子抑制剂。前期我们通过虚拟筛选获得一蝶啶类EGFR抑制剂先导化合物~([3,4]),优化设计并合成了一系列衍生物。之后我们通过分子水平酶活实验获得一些选择性抑制剂,其中化合物E01对EGFR~(L858R/T790M)和EGFR~(WT)的半数抑制浓度(IC_(50))分别为2.6 nM和131.9 nM;接着细胞自磷酸化实验结果显示E01在H1975细胞株(EGFR-L858R/T790M)和A431细胞株(EGFR-WT)中自磷酸化活性的半数抑制浓度(IC_(50))分别为5.2 nM和160 nM。以上实验结果表明化合物E01对于EGFR~(L858R/T790M)突变体具有较高抑制活性,且其选择性达30-50倍。本研究可为EGFR突变体小分子抑制剂的开发提供基础,以期获得靶向EGFR突变体的高选择性的抑制剂。
Epidermal growth factor receptor(EGFR) is a kind of receptor tyrosine kinase,its abnormal activation and overexpression lead to tumor occurrence.Gefitinib and erlotinib play an important role in the treatment of non-small-cell lung cancer(NSCLC).However,most NSCLC patients developed acquired resistance to EGFR TKIs after a time,our group is committed to the development of highly active and selective EGFR TKIs.In the previous work we have developed a pteridine class of EGFR inhibitor,the subsequent design and optimization led to a series of selective inhibitors and compound E01 exhibited enzyme activity with IC_(50)value of 0.2 nM for EGFR ~(L858R/T790M) mutant and 131.9 nM for wild EGFR,as well as cellular autophosphorylation activities with IC_(50) value of 5.2 nM against H1975 cell(EGFR-L858R/T790M) and 160 nM,against A431 cell(EGFR-WT),respectively.The above results show that compound E01 highly inhibits EGFR ~(L858R/T790M) mutant,and its selectivity reaches 30 to 50 times.This study can provide the basis for developing highly selective mutant EGFR inhibitors.
Epidermal growth factor receptor(EGFR) is a kind of receptor tyrosine kinase,its abnormal activation and overexpression lead to tumor occurrence.Gefitinib and erlotinib play an important role in the treatment of non-small-cell lung cancer(NSCLC).However,most NSCLC patients developed acquired resistance to EGFR TKIs after a time,our group is committed to the development of highly active and selective EGFR TKIs.In the previous work we have developed a pteridine class of EGFR inhibitor,the subsequent design and optimization led to a series of selective inhibitors and compound E01 exhibited enzyme activity with IC_(50)value of 0.2 nM for EGFR ~(L858R/T790M) mutant and 131.9 nM for wild EGFR,as well as cellular autophosphorylation activities with IC_(50) value of 5.2 nM against H1975 cell(EGFR-L858R/T790M) and 160 nM,against A431 cell(EGFR-WT),respectively.The above results show that compound E01 highly inhibits EGFR ~(L858R/T790M) mutant,and its selectivity reaches 30 to 50 times.This study can provide the basis for developing highly selective mutant EGFR inhibitors.
引文
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[2]Jackman D.;Pao W.;Riely GJ.J Clin Oncol.2010,28(2):357.
[3]Zhou W.;Liu X.;Xu Y.;Li H.J.Med.Chem.2013,56(20):7821.
[4]Bai F.;Li H.Bioorg.Med.Chem.Lett.2012,22(3):1365.