An irreversible inhibitor of peptidyl-prolyl cis/trans isomerase Pin1 and evaluation of cytotoxicity |
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| Authors: | Naoya Ieda Kaoru Itoh Yasumichi Inoue Yusuke Izumiya Mitusyasu Kawaguchi Naoki Miyata Hidehiko Nakagawa |
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| Affiliation: | 1. Graduate School of Pharmaceutical Sciences, Nagoya Citi University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan;2. Faculty of Pharmaceutical Sciences, Nagoya Citi University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan |
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| Abstract: | Pin1 (protein interacting with never in mitosis A-1) is a member of the peptidyl prolyl isomerase (PPIase) family, and catalyzes cis-trans isomerization of pThr/Ser-Pro amide bonds. Because Pin1 is overexpressed in various cancer cell lines and promotes cell growth, it is considered a target for anticancer agents. Here, we designed and synthesized a covalently binding Pin1 inhibitor (S)-2 to target Pin1’s active site. This compound inhibited Pin1 in protease-coupled assay, and formed a covalent bond with Cys113 of Pin1, as determined by ESI-MS. The acetoxymethyl ester of (S)-2, i.e., 6, suppressed cyclin D1 expression in human prostate cancer PC-3 cells, and exhibited cytotoxicity. Pin1-knockdown experiments indicated that a target for the cytotoxicity of 6 is Pin1. |
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| Keywords: | Peptidyl prolyl isomerase Irreversible inhibition Covalent bond Michael acceptor Cysteine |
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