以分泌型热休克蛋白90α为靶标的抗癌化合物的设计、合成和活性评价

项目名称： 以分泌型热休克蛋白90α为靶标的抗癌化合物的设计、合成和活性评价

项目编号： No.81473085

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 宋淳

作者单位： 山东大学

项目金额： 85万元

中文摘要： 热休克蛋白(Hsp90)是ATP依赖性的分子伴侣，参与客户蛋白的激活和成熟，与细胞的增殖、凋亡、癌变和肿瘤发展密切相关。热休克蛋白90有α和β两细胞质亚型，近年来研究发现，许多Hsp90抑制剂造成的毒副作用可能与缺乏对Hsp90α亚型的选择性有关。Hsp90α又分为分泌型和内源型两种，而分泌型eHsp90α在某些特定肿瘤中高表达并且其抑制剂可以有效阻止肿瘤细胞迁移，这一发现激发了选择性eHsp90α抑制剂研究的浪潮。本项目申请是在课题组对这一靶点多年研究的基础上结合当前生物和临床研究的最新发现，通过计算机分子模拟设计，结合对特定种类Hsp90α的体外体内测试，寻找细胞通透能力差的，可以选择性抑制eHsp90α亚型的小分子抑制剂。研究目标是对eHsp90α在不同肿瘤中的表达和功能进一步研究的同时，创制毒副作用较低同时有效阻止肿瘤细胞迁移的选择性抑制eHsp90α的抗癌药物候选化合物。

中文关键词： 计算机辅助药物设计；药物设计与合成；抗肿瘤药物；抗肿瘤活性；构效关系

英文摘要： Heat Shock protein 90 (Hsp90) is an ATP-dependent chaperone protein that assists the conformational activation and maturation of a large number of client proteins. Hsp90 has been known to be closely related to cell proliferation and apoptosis, and be required for oncogene-mediated transformation and tumor development. Vertebrates have two Hsp90 genes - Hsp90α and Hsp90β. Some studies suggest that the cytotoxicity of many Hsp90 inhibitors results from their lack of selectivity against Hsp90α. More recently, it was demonstrated that Hsp90α is composed of the secreted extracellular form (eHsp90α) and the intracellular form. The identification of eHsp90α has attracted worldwide attention in the field and triggered new wave of research on inhibitors of heat shock proteins. Based on the substantial progress we have made during the last several years and the new opportunities afforded through recent advances in our understanding of Hsp90 biology, we herein propose to develop membrane-impermeable chemical inhibitors of eHsp90α through our well-established computer aided molecular design system and in vitro and in vivo testing models. The overall goal of our proposal is to study the expression and function of eHsp90α in different types of tumor cells, and to identify novel specific inhibitors for Hsp90α as drug candidates.

英文关键词： computer-aided drug design;drug design and synthesis;Antitumor drugs;antitumor activity;Structure-activity relationship