热休克转录因子HSF1选择性抑制剂的设计、合成及抗肿瘤作用机制研究

热休克转录因子HSF1通过促进热休克蛋白(HSPs)的表达，以保护相关蛋白的正确折叠，对高胁迫环境下肿瘤细胞的生存极其重要，是当前备受关注的潜在抗癌新靶点。但HSF1缺乏天然底物，至今仍缺乏特异性的HSF1直接抑制剂，无确切的HSF1抑制活性位点信息。针对此难点，申请人前期通过高内涵筛选获得先导物QEC29，它能降解和下调多种HSPs客户蛋白，并能阻断因HSP90抑制剂负反馈作用引起的HSPs高表达，进而防止肿瘤耐药；进一步通过靶点垂钓实验，证实QEC29是一种新型HSF1直接抑制剂。本项目将在此基础上，运用多学科技术手段深入研究并阐明该化合物与HSF1的互作位点和作用机制；基于配体和靶点信息进行理性的药物设计与合成，构建活性化合物库；改进高内涵筛选系统用于活性评价，总结构效关系，发现活性、特异性更佳及机制明确的HSF1抑制剂，为基于HSF1为靶点发展新型抗肿瘤药物提供理论基础和科学依据。

Heat shock transcription factor HSF1 plays an important role in the survival of tumor cells under high stress enviroment by promoting the expression of HSPs (Heat Shock Proteins) to protect the correct folding of relevant proteins. Therefore, HSF1 is a novel potential anti-tumor target. However, there is no native substrate for HSF1, so far, there is also no exact information about the active pocket of HSF1, and there is a lack of specific direct inhibitor of HSF1. To solve this problem, in the early work, the applicant obtained the lead compound QEC29 through high-content screening, which can degrade and downregulate a variety of client proteins of HSPs, and can block the tumor resistance caused by the negative feedback of HSP90 inhibitor to induce the high expression of HSPs. QEC29 is confirmed as a novel direct inhibitor of HSF1 by pull-down experiment of protein. We will use multidisciplinary techniques and methods to further investigate and elucidate the interaction site and mechanism of the compound with HSF1. A rational drug design and modification are carried out based on the information of ligands and targets to construct the active compound library; The high-content screening system was improved to evaluate the activity and the structure-activity relationships. Aim to obtain more active and specific HSF1 inhibitors. These will provide a theoretical and scientific basis for the development of novel anti-tumor drugs based on HSF1 as the target.