文献类型：期刊文献

英文题名：Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration

作者：Jiang, Haiming[1];Deng, Rong[1,2];Yang, Xiuyan[1];Shang, Jialin[1];Lu, Shaoyong[1];Zhao, Yanlong[1];Song, Kun[1];Liu, Xinyi[1,3];Zhang, Qiufen[1,3];Chen, Yu[4];Chinn, Y. Eugene[5,6];Wu, Geng[7];Li, Jian[8];Chen, Guoqiang[1,5,6];Yu, Jianxiu[1,2];Zhang, Jian[1,3]

机构：[1]Shanghai Jiao Tong Univ, Sch Med, Minist Educ, Dept Pathophysiol,Key Lab Cell Differentiat & Apo, Shanghai, Peoples R China;[2]Shanghai Jiao Tong Univ, Sch Med, Shanghai Key Lab Tumor Microenvironm & Inflammat, Dept Biochem & Mol Cell Biol,State Key Lab Oncoge, Shanghai, Peoples R China;[3]Shanghai Jiao Tong Univ, Sch Med, Med Bioinformat Ctr, Shanghai, Peoples R China;[4]Chinese Acad Sci, Shanghai Inst Ceram, State Key Lab High Performance Ceram & Superfine, Shanghai, Peoples R China;[5]Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai, Peoples R China;[6]Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China;[7]Shanghai Jiao Tong Univ, State Key Lab Microbial Metab, Shanghai, Peoples R China;[8]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China

年份：2017

卷号：13

期号：9

起止页码：994

外文期刊名：NATURE CHEMICAL BIOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000407929800017)】；

基金：We sincerely thank T. Akiyama (University of Tokyo) for help with the cell migration assay and for fruitful discussions on application, S. Wang (University of Michigan) for design discussion and antibody shipping, and the Shanghai Synchrotron Radiation Facility (SSRF) for crystal diffraction. APC, Asef and full-length CDC42 were kind gifts from G. Wu (Shanghai Jiao-Tong University, Shanghai, China). This work was supported in part by the National Basic Research Program of China (973 Program) (grant 2015CB910403 to J.Z.), the National Natural Science Foundation of China (grants 81630075 to J.Y., 81322046 and 81473137 to J.Z., and 81302698 to S.L.), the Innovative Research Group of NSFC (J.Z., J.Y. and G.C.), the Shanghai Rising-Star Program (grant 13QA1402300 to J.Z.), the Shanghai Sailing Program (grant 17YF1410600 to X.Y.), the National Program for Support of Top-notch Young Professionals (grant 2015 to J.Z.), and the Program for New Century Excellent Talents in University (grant NCET-12-0355 to J.Z.).

语种：英文

摘要：The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC-Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal cancer cells. Our work demonstrates the feasibility of exploiting APC-Asef interaction to regulate the migration of colorectal cancer cells, and provides what to our knowledge is the first class of protein-protein interaction inhibitors available for the development of cancer therapeutics targeting APC-Asef signaling.