一种肽基脯氨酰顺/反式异构酶 Pin1 的不可逆抑制剂及其细胞毒性评价。
An irreversible inhibitor of peptidyl-prolyl cis/trans isomerase Pin1 and evaluation of cytotoxicity.
机构信息
Graduate School of Pharmaceutical Sciences, Nagoya Citi University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
Faculty of Pharmaceutical Sciences, Nagoya Citi University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
出版信息
Bioorg Med Chem Lett. 2019 Feb 1;29(3):353-356. doi: 10.1016/j.bmcl.2018.12.044. Epub 2018 Dec 19.
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.
Pin1（与有丝分裂 A-1 中永不结合的蛋白）是肽基脯氨酰顺反异构酶（PPIase）家族的一员，能够催化 pThr/Ser-Pro 酰胺键的顺反异构化。由于 Pin1 在各种癌细胞系中过表达，并促进细胞生长，因此被认为是抗癌药物的靶点。在这里，我们设计并合成了一种共价结合的 Pin1 抑制剂（S）-2，以靶向 Pin1 的活性位点。该化合物在蛋白酶偶联测定中抑制 Pin1，并通过 ESI-MS 确定与 Pin1 的 Cys113 形成共价键。（S）-2 的乙酰氧甲基酯，即 6，抑制人前列腺癌 PC-3 细胞中环细胞 D1 的表达，并表现出细胞毒性。Pin1 敲低实验表明，6 的细胞毒性的靶标是 Pin1。
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