热休克蛋白Hsp90是肿瘤发生发展过程中的关键分子之一，而现有Hsp90抑制剂临床疗效并不理想。本项目核心是开发选择性靶向热休克蛋白内质网亚型Grp94蛋白抑制剂，以期能克服传统Hsp90抑制剂的缺点。主要研究思路是基于诱导契合策略合理开发兼顾活性和选择性的亚型抑制剂。即在整合优势骨架基础上进行分子片段生长，诱导Grp94ATP口袋结构中苯丙氨酸（Phe199）发生位移，占据暴露的新疏水口袋，开展抑制剂开发。同时考察抑制剂与靶标结合过程中的选择性行为、结合动力学和热力学行为以及理化性质参数等，最终获得具有结构新颖活性明确的调控剂，并以此为探针分子，利用化学生物学、分子生物学等相关技术深入挖掘Grp94介导肿瘤炎症微环境的产生和炎-癌转化网络的关键节点作用，探索选择性抑制Grp94的治疗学效应。本项目综合运用多种技术，发挥交叉学科优势，为从炎-癌转化角度诊治肿瘤提供新的调控剂和药物靶点。

Heat shock protein 90（Hsp90） is one of the key roles that stands at the center of oncogenic proteostasis. However, the clinic effect of Hsp90 inhibitors are disappointing. In this project, we aim to develop Grp94-selective inhibitor in ER to avoid the defects of the traditional pan-Hsp90 inhibitors. Designing the inhibitor with activity and selectivity based on the induced fit strategy is chosen as the main research idea. To develop the selective inhibitor, the method is to design the fragment from the good scaffold based on the induced fit strategy in order to induce and occupy the hydrophobic pocket by moving Phe199 in the ATP pocket of Grp94. After that, based on the binding physical chemistry disciplines, microscopic intermolecular interactions, macroscopic physical chemistry effects and detailed molecular properties can be coordinated to evaluate and optimize the Grp94 inhibitors. Combining the techniques from chemical biology and molecular biology, the Grp94 inhibitors will be used as molecular probe to identify novel regulatory mechanism of Grp94 benfit the drug development process in tumor cells as well as the development of tumor inflammatory microenvironment. The project will provide new insight into the role of Grp94 in the development of chronic inflammation and cancer and new strategies for developing cancer therapeutics targeting Grp94.