新型丙酮酸激酶M2亚型（PKM2）激动剂的设计、合成及构效关系研究

项目名称： 新型丙酮酸激酶M2亚型（PKM2）激动剂的设计、合成及构效关系研究

项目编号： No.81502905

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李日东

作者单位： 北京大学

项目金额： 17.9万元

中文摘要： 基于肿瘤细胞代谢的特殊性，选择性地干预肿瘤细胞代谢过程中的关键环节，有可能达到既不损伤正常细胞，又可以抑制肿瘤细胞增殖的目的。糖代谢异常是肿瘤细胞的一个重要特征（Warburg 效应）。丙酮酸激酶的M2亚型（PKM2）在肿瘤细胞中显著高表达，且在肿瘤细胞异常代谢过程中起重要作用。PKM2主要以高活性的四聚体和低活性的二聚体这两种形式存在，四聚体型PKM2主要存在于正常细胞中，而二聚体型PKM2主要存在于肿瘤细胞中。因此，设计、合成有效的PKM2激动剂可使低活性的PKM2转化成高活性的PKM2，既可抑制癌症发生的进程，又对正常细胞没有损伤。苗头化合物A是从我们化合物库中筛选出的结构全新的PKM2激动剂。本课题选择PKM2为靶点，将化合物A分为三部分进行结构优化，通过计算机虚拟筛选、合成、活性评价等系统研究，以期发现新结构类型的高效PKM2激动剂。

中文关键词： 合成药物化学；PKM2激动剂；抗肿瘤；丙酮酸激酶

英文摘要： Based on the particularity of tumor cell metabolism, selectively interrupting the key step of tumor cell metabolism could inhibit the proliferation of tumor cells without damaging normal cells. Abnormal glucose metabolism is one of the important characteristics of tumor cells (Warburg effect). Pyruvate kinase M2 isoform (PKM2) in tumor cells is significantly higher expressed, and plays an important role in the process of abnormal metabolism of tumor cells. PKM2 exists in equilibrium between less active dimeric form and highly active tetrameric form. The low activity dimeric form is mainly presented in normal cells; but the high activity tetrameric form exists predominantly in tumor cells. Therefore, the effective PKM2 activators could induce the low activity states of PKM2 into the active state of the PKM2 which will not only inhibit the growth of tumor cells, and do not produce the poisonous side effect. Hit compound A is a new structure of PKM2 activators screened out from our compound library. In this study, we will select PKM2 as target and optimize the structure of hit A by dividing it into three parts. The systemic optimization includes virtual screening, synthesis, activity evaluation. The aim of this work is to find the efficient PKM2 activators.

英文关键词： Synthetic medicinal chemistry;PKM2 activators;Antitumor;Pyruvate kinase