靶向肾癌中的E3连接酶接头蛋白SPOP的小分子抑制剂  

Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer

作　　者：Zhong-Qiang Guo Tong Zheng Baoen Chen Cheng Luo Sisheng Ouyang Shouzhe Gong Jiafei Li Liu-Liang Mao Fulin Lian Yong Yang Yue Huang Li Li Jing Lu Bidong Zhang Luming Zhou Hong Ding Zhiwei Gao Liqun Zhou Guoqiang Li Ran Zhou Ke Chen Jingqiu Liu Yi Wen Likun Gong Yuwen Ke Shang-Dong Yang Xiao-Bo Qiu Naixia Zhang Jin Ren Dafang Zhong 杨财广 刘江[3,4,5] 蒋华良[2,6] 

机构地区：[1]不详 [2]中国科学院上海药物研究所 [3]中国科学院北京基因组研究所 [4]中国科学院学术委员会 [5]发展中国家科学院 [6]中国科学院新药研究国家重点实验室

出　　处：《科学新闻》2017年第4期59-59,共1页Science News

基　　金：国家自然科学基金委;科技部;中科院等有关项目的资助

摘　　要：近年来肾癌发病率上升幅度在恶性肿瘤中排名第一。临床治疗表明，肾癌对放疗和化疗均不敏感，以索拉非尼和舒尼替尼为代表的靶向抗肿瘤药物是晚期肾癌的一线治疗药物，但对转移性肾癌的疗效十分有限，并且容易产生耐药。因此，发现并确证治疗肾癌特异性药物作用新靶标是一项十分紧迫并意义重大的任务。In the cytoplasm of virtually all clear-cell renal cell carcinoma (ccRCC), speckle-type POZ protein (SPOP) is overexpressed and misallocated, which may induce proliferation and promote kidney tumorigenesis. In normal cells, however, SPOP is located in the nucleus and induces apoptosis. Here we show that a structure-based design and subsequent hit optimization yield small molecules that can inhibit the SPOP-substrate protein interaction and can suppress oncogenic SPOP-signaling pathways. These inhibitors kill human ccRCC cells that are dependent on oncogenic cytoplasmic SPOP. Notably, these inhibitors minimally affect the viability of other cells in which SPOP is not accumulated in the cytoplasm. Our findings validate the SPOP-substrate protein interaction as an attractive target specific to ccRCC that may yield novel drug discovery efforts.

关 键 词：抑制剂 分子 蛋白 接头 连接 临床治疗 治疗药物 抗肿瘤药物 

分 类 号：TU755.32[建筑科学—建筑技术科学]