亚型特异性Hsp70抑制剂的设计合成、和抗肿瘤分子标志物研究

虽然热休克蛋白70（Hsp70）早已被确认为癌症靶标，但是其抑制剂仍然没有进入临床。Hsp70家族的亚型蛋白，Hsp70/Hsc70、Grp75、和 Grp78等，分别定位于不同的细胞器。它们的生理功能可以相互代偿，却可能介导了不同的肿瘤信号转导通路。本研究拟在自主研发的、荧光发光的Hsp70蛋白别构抑制剂的基础上，或者将其连接不同亚细胞定位基团，或者根据其明确的结合位点以及不同Hsp70亚型蛋白在其结合位点附近的结构差异设计衍生物，选择性结合多种Hsp70亚型蛋白。通过化学蛋白质组学和生物信息学方法，原位、可视化确认Hsp70亚型蛋白在不同肿瘤细胞中的靶标地位，在获得高效、低毒、体内抗肿瘤的亚型特异性Hsp70抑制剂的同时，发现其抗肿瘤分子机制，鉴定其抗肿瘤分子标志物，实现靶标确认—抑制剂研发—分子标志物鉴定的一体化研究。

The Hsp70s have been certified as cancer targets. However, none of the Hsp70 inhibitors has entered the clinical trial, and the expression level of Hsp70s has not yet been accepted as a biomarker of any cancer parameter. The Hsp70 paralogs, including Hsc70, Hsp70, Grp75 and Grp78, have different subcellular locations and are related to cancer initiation and development. Moreover, it is now recognized that the housekeeping role of each paralog can be compensated by the others, while each paralog has a unique biochemical role in regualting specific cancer sigaling The Hsp70s have been certified as cancer targets. However, none of the Hsp70 inhibitors has entered the clinical trial, and the expression level of Hsp70s has not yet been established as an anti-cancer biomarker. The Hsp70 paralogs, including Hsc70, Hsp70, Grp75 and Grp78 with different subcellular location are related to cancer initiation and development. Moreover, it is now recognized that the housekeeping role of each paralog can be compensated by the others, while each paralog has a unique biochemical role in regulating specific cancer signaling pathways. Therefore, development of paralog-selective Hsp70 inhibitors offers an opportunity for effective and hypotoxic cancer treatment. Herein, on the basis of the allosteric Hsp70s inhibitor S1g developed by our group, we plan to design and synthesis i) subcellualar-selective Hsp70 inhibitors by conjugating subcellular targeting groups to S1g; or ii) paralog-selective Hsp70 inhibitors by incorporating substituents to S1g according to the structural information and residue characterization around S1g's binding site of each paralog. Then, the candidate molecules will be screened via in vitro assays, cellular biological assays and animal experiments to gain lead compounds that exhibit effective and hypotoxic anti-cancer activity via inhibiting unique Hsp70 paralogs. Simultaneously, we plan to investigate the biomarkers of the anti-cancer susceptibility of these lead compounds by chemical proteomic and bio-informatics assays, in order to improve the drug approve in the future.