靶向VEGFR-2的II型小分子抑制剂的设计、合成及构效关系研究

项目名称： 靶向VEGFR-2的II型小分子抑制剂的设计、合成及构效关系研究

项目编号： No.81202413

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 伍小云

作者单位： 南方医科大学

项目金额： 23万元

中文摘要： 血管内皮生长因子受体-2(VEGFR-2)抑制剂是一种新型的抗肿瘤药物。目前开发的大部分抑制剂是I型抑制剂，深入到ATP结合位点，激酶处于"DFG-in"活性构象，存在选择性差、副作用大等缺点。II型抑制剂诱导位于激酶活化区域保守的DFG序列的运动，激酶处于"DFG-out"非活性构象，并且暴露出一个额外的疏水口袋(变构位点)。除了与ATP结合位点结合外，II型抑制剂还与变构位点结合，因此，具有更高的选择性和有效性。基于激酶非活性"DFG-out"构象的晶体结构和II型抑制剂的药效团模型，本研究将以吡唑并[3,4-d]嘧啶为铰链区结合骨架，设计、合成一系列结构新颖的化合物，测定化合物生物活性，建立三维定量构效关系(3D-QSAR)模型，以指导进一步VEGFR-2抑制剂的研发。

中文关键词： 血管内皮生长因子受体-2；II型抑制剂；吡唑并[3;4-d]嘧啶衍生物；分子模拟；合成

英文摘要： Vascular endothelial growth factors receptor-2 inhibitors have been proved as very effective anticancer agents.The vast majority of the known VEGFR-2 inhibitors to date are classified as type I inhibitors. Such inhibitors target the ATP binding pocket in its active conformation of the activation loop. This conformation is normally referred to as DFG "in" based on the position of the conserved triad aspartate-phenylalanine-glycine (DFG) at the entrance of the activation loop. In response to these issues, type II inhibitors bind to and stabilize an inactive kinase form that features the DFG motif in an "out" conformation. The different position of the DFG residues in the "out" form creates a new hydrophobic binding pocket that is adjacent to the ATP-binding site. This pocket, also known as the allosteric site, is characteristic of kinase in an inactive conformation. Compared with type I kinase inhibitors, type II inhibitors have several advantages, including great cellular potency and improved kinase selectivity. Based on the crystal structure of the kinase inactive DFG"out"conformation and type II kinase inhibitors pharmacophore, this study will design,synthesis a series of novel compounds with the pyrazolo[3,4-d]pyrimidine scaffold as a novel kinase hinger binding template, evalute the biological activities，a

英文关键词： Vascular endothelial growth factors receptor-2；type II inhibitors；pyrazolo[3;4-d]pyrimidine derivatives；molecular modeling；synthesis