电喷雾质谱法研究抗癌先导药物与FAK蛋白的相互作用及机制

项目名称： 电喷雾质谱法研究抗癌先导药物与FAK蛋白的相互作用及机制

项目编号： No.21275167

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 王献

作者单位： 中南民族大学

项目金额： 80万元

中文摘要： 粘附斑激酶(FAK)蛋白与癌细胞侵袭、转移、发生行为密切相关，是一个肿瘤治疗的潜在靶点。FAK的抑制剂分子能够有效抑制FAK活性，并显示对肿瘤细胞增殖和迁移有明显的抑制效果。因此，本课题拟针对FAK特异性抑制剂的研究和筛选，发展并构建质谱学新方法，包括设计新的在线反应和氢氘交换（H/D exchange）时间分辨电喷雾质谱法（Time-resolved ESI mass spectrometry），研究和测定FAK、FAK的结构功能域与抑制剂分子的相互作用，表征抑制作用过程中FAK蛋白质构象的动态变化，确定抑制剂和FAK蛋白相互作用的具体区域和作用位点,以阐明FAK抑制剂的作用机制。本项目所建立的方法可以应用于新FAK抑制剂的筛选和考察，为寻找以FAK为靶点的抑制癌细胞侵袭转移的新药物前体分子提供新的方法和途径。

中文关键词： 电喷雾质谱；FAK蛋白－抑制剂相互作用；氢氘交换质谱；药物筛选；体外代谢规律

英文摘要： FAK (Focal adhesion kinase) protein plays important roles in cancer cell invasion, migration and carcinogenesis, and it is thereby considered as a potential target in cancer therapy. Small molecule inhibitors targeting FAK can effectively inhibit the activity of FAK and have shown in many researches the inhibitive effects on apoptosis and migration of various tumor cells. Hence, this work is proposed to develop novel mass spectrometry methods, including the design of a new on-line reaction and hydrogen-deuterium exchange (H/D exchange) time-resolved electrospray ionization mass spectrometry, to study and characterize the interactions between inhibitor molecules and FAK protein or its functional domains. We will also probe the dynamic conformational changes of FAK protein during the inhibition process in order to explore the mechanism of FAK inhibitor, and initially identify the specific interaction sites of inhibitors and FAK protein. The methods established in this project can be applied to the screening and investigation of new FAK inhibitors, and also provide new approaches to discover new drug precursor molecules targeting FAK for the inhibition of cancer cell invasion and migration.

英文关键词： Electrospray ionization mass spectrometry (ESI-MS)；FAK protein-inhibitor interactions；Hydrogen-deuterium exchange mass spectrometry；Drug screening；in vitro metabolism