EGFR(T790M)抑制剂的设计、合成及活性评价

表皮生长因子受体(EGFR)的T790M突变最为频发,也是肺癌临床治疗失败的主要原因之一。鉴于先导化合物B6优良的抗H1975细胞系和异植瘤活性,对其进行了EGFR(T790M)激酶抑制活性的确认,并使用Autodock软件确认了两者的相互作用。以EGFR(T790M)为靶点对B6进行定向结构修饰,所得目标化合物经NMR和MS表征后,联合体外激酶、细胞生物活性与Autodock软件解释它们的构效关系。结果表明,3-(苯并d]1,3]二氧杂-5-基)-1-(1-(乙烯基磺酰基)哌啶-4-基)-1H-吡唑并3,4-d]嘧啶-4-胺的抗H1975细胞增殖活性(IC₅₀=(1.16±0.24)μmol/L)与B6(IC₅₀=(0.91±0.36)μmol/L)相似,尽管其对EGFR(T790M)的抑制活性(IC₅₀=(148.2±7.2)nmol/L)不如B6(IC₅₀=(22.0±2.6)nmol/L)。以7H-吡咯并2,3-d]嘧啶-4-胺为母核,取代基分别为胡椒环基和4-取代哌啶基者可开发活性更优的EGFR(T790M)抑制剂,指导后期研究。

Study of Design,Synthesis and Bioactivity Evaluationfor EGFR(T790M)Inhibitors

The mutation of T790M in Epidermal growth factor receptor(EGFR)is the most frequent,which also is the main reason for the failure of lung cancer′s clinical treatments.In view of the previous study,lead compound B6 displayed the good anti-proliferation against H1975 cell line and inhibited the growth of H1975 xenograft tumor,this article confirmed its inhibitory activity against EGFR(T790M),as well as explained their interaction by Autodock.Then we carried out the structural modifications for B6 aiming at the target of EGFR(T790M).All the targete compounds obtained were characterized by NMR and MS.The structure-activity relationship was analyzed by Autodock based on the bioactivity evaluation of kinase and cell levels.The results showed that only compound 3-(benzod]1,3]dioxol-5-yl)-1-(1-(vinylsulfonyl)piperidin-4-yl)-1H-pyrazolo3,4-d]pyrimidin-4-amine exhibited similar anti-proliferation activity against H1975 cell line(IC₅₀=(1.16±0.24)μmol/L)to B6(IC₅₀=(0.91±0.36)μmol/L),although its inhibition against EGFR(T790M)(IC₅₀=(148.2±7.2)nmol/L)was weaker than B6(IC₅₀=(22.0±2.6)nmol/L).Comprehensive analysis indicated that that compounds with 7H-pyrrolo2,3-d]pyrimidin-4-amine as the core,and substituted with piperonyl and 4-substituted piperidinyl may get EGFR(T790M)inhibitors with good bioactivity,which could guide later research.