基于受体结构的新型氮杂吲哚-2-酮类FGFR1抑制剂的设计、合成及抗肿瘤活性研究

项目名称： 基于受体结构的新型氮杂吲哚-2-酮类FGFR1抑制剂的设计、合成及抗肿瘤活性研究

项目编号： No.21202124

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 有机化学

项目作者： 刘志国

作者单位： 温州医科大学

项目金额： 25万元

中文摘要： 成纤维生长因子受体(FGFR) 介导的信号转导途径参与肿瘤细胞形成和发展过程，而FGFR抑制剂能阻断信号传导的某个环节，达到抑制肿瘤发生、发展的目的。临床已有部分FGFR抑制剂应用于肿瘤治疗，如吲哚-2-酮类化合物SU5402等，但它们主要结合于受体口袋的中部或外侧，缺乏对激酶的选择性，显示出多种毒副作用。我们前期发现 FGFR1 结合口袋内部存在特异性的氨基酸序列和结构，相异于其他激酶。本项目中，我们基于SU5402在FGFR1结合口袋的作用模式，针对结合域内部特有的空间和氨基酸序列设计并合成高效氮杂吲哚-2-酮类FGFR1选择性抑制剂；测试该类抑制剂对FGFR1和其他激酶的抑制，表征体内外抗肿瘤活性，通过siRNA技术明确其作用靶点，并辅以分子对接技术和ATP竞争实验确证与FGFR1的结合模式和位点。本项目将为以FGFR1为靶标的抗肿瘤药物研究提供新的作用位点和新型选择型高效抑制剂。

中文关键词： 成纤维生长因子受体；吲哚-2-酮；抑制剂；合成；活性

英文摘要： The singaling pathway induced by Fibroblast growth factor receptor (FGFR1) plays sasignificant role in tumor is relative to the tumor angiogenesis, transplantation, division and proliferation, while the FGFR1 inhibitor can markedly block one step of above signals thereby prevent the tumor. There are several FGFR1 inhibitors have currently used in clinical trials for cancer treatment, most inhibitors bind to the middle and outer of relatively conserved ATP-binding domain in RTKs and lack kinase selectivity, which gives rise to a variety of side and toxic effects. we found through computer-assisted analysis that the ATP-binding sites in currently available inhibitors account for only a fraction of the ATP-binding pocket in the FGFR1 protein and are localized in the middle and outside within the cavity of the whole ATP-binding pocket, it is different from other RTKs. As one of FGFR1 inhibitors, compound SU5402 displayed the significantly selective inhibitory effect. In our project, based on this finding and the amino acid sequence inside of ATP-binding pocket, we plan to design and synthesize a series of potent azaindolin-2-one FGFR1 inhibitors and further explore the structure-activity relationship on 3 position of the core which never be explored before. Meanwhile, several inhibitors will be choosed to test the i

英文关键词： FGFR；Indolin-2-one；Inhibitor；Synthesis；Activity