标题：Discovery of a fluorescent probe with HDAC6 selective inhibition
作者：Zhang, Yingjie; Yan, Jin; Yao, Tso-Pang
作者机构：[Zhang, Yingjie] Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Jinan 250012, Shandong, Peoples R China.; [Zhang, Yingjie] Shandong Univ, Sch Pha 更多
通讯作者：Zhang, YJ;Yao, TP
通讯作者地址：[Zhang, YJ]Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Jinan 250012, Shandong, Peoples R China;[Yao, TP]Duke Univ, Dept Pharmacol & Canc Biol, D 更多
来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
关键词：HDAC6; Fluorescent probe; Aggresome; Neurodegenerative disease
摘要：There is increasing interest in discovering HDAC6 selective inhibitors as chemical probes to elucidate the biological functions of HDAC6 and ultimately as new therapeutic agents. Small-molecular fluorescent probes are widely used to detect target protein location and function, identify protein complex composition in biological processes of interest. In the present study, structural modification of the previously reported compound 4MS leads to two novel fluorescent HDAC inhibitors, 6a and 6b. Determination of IC50 values against the panel of Zn2+ dependent HDACs (HDAC1-11) reveals that 6b is a HDAC6 selective inhibitor, which can induce hyperacetylation of tubulin but not histone H4. Importantly, fluorescent and immunofluorescent analyses of cells treated with the proteasome inhibitor MG132 demonstrates that 6b can selectively target and image HDAC6 within the inclusion body, the aggresome. These results identify 6b not only as a HDAC6 selective inhibitor but also as a fluorescent probe for imaging HDAC6 and investigating the roles of HDAC6 in various physiological and pathological contexts. (C) 2017 Elsevier Masson SAS. All rights reserved.