Discovery of a fluorescent probe with HDAC6 selective inhibition

European Journal of Medicinal Chemistry
Yingjie ZhangTso-Pang Yao

Abstract

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.

Citations

Aug 14, 2018·Analytical and Bioanalytical Chemistry·Yudai Tabuchi, Masumi Taki
Sep 1, 2018·Organic & Biomolecular Chemistry·Yi-Hsun HoChao-Wu Yu
May 21, 2020·Chemical Communications : Chem Comm·Elley E RudebeckFrederick M Pfeffer
Jun 20, 2021·Bioorganic & Medicinal Chemistry Letters·Sasha Padilla-ColeyFrederick M Pfeffer
Sep 17, 2021·Organic & Biomolecular Chemistry·Yinyu YanWei Li
Oct 7, 2021·Chemical Communications : Chem Comm· RoopaNaresh Kumar

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