Dipentamethylene thiuram monosulfide is a novel inhibitor of Pin1
Dipentamethylene thiuram monosulfide is a novel inhibitor of Pin1
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DOI：
10.1016/j.bbrc.2009.04.144
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发表时间：
2009-07-03
影响因子：
3.1
通讯作者：
Uchida, Takafumi
中科院分区：
文献类型：
--
作者：
Tatara, Yota;Lin, Yi-Chin;Uchida, Takafumi
Pin 1通过改变磷酸化蛋白的结构和功能参与真核细胞增殖。Pin 1特异性抑制剂PiB可阻断癌细胞增殖。然而，PiB在DMSO中的低溶解度限制了对其有效性的研究。我们筛选了其他Pin I抑制剂，并鉴定了DMSO可溶性化合物双五亚甲基秋兰姆单硫化物（DTM），其抑制Pin 1活性的EC 50值为4.1 μ M。分子模拟和酶动力学分析表明，DTM竞争性抑制Pin 1活性，Ki值为0.05 μ M。用SPR技术测定DTM与Pin 1的K-D值为0.06 μ M。此外，DTM特异性地抑制HeLa细胞中的肽基脯氨酰顺/反异构酶活性。流式细胞仪分析显示DTM诱导HCT 116细胞G 0期阻滞。我们的研究结果表明，DTM有可能指导新的抗真菌和/或抗癌药物的开发。(C)2009 Elsevier Inc. All rights reserved.
Pin1 is involved in eukaryotic cell proliferation by changing the structure and function of phosphorylated proteins. PiB, the Pin1 specific inhibitor, blocks cancer cell proliferation. However, low solubility of PiB in DMSO has limited studies of its effectiveness. We screened for additional Pin I inhibitors and identified the DMSO-soluble compound dipentamethylene thiuram monosulfide (DTM) that inhibits Pin1 activity with an EC50 Value of 4.1 mu M. Molecular modeling and enzyme kinetic analysis indicated that DTM competitively inhibits Pin1 activity, with a K-i value of 0.05 mu M. The K-D value of DTM with Pin1 was determined to be 0.06 mu M by SPR technology. Moreover, DTM specifically inhibited peptidyl-prolyl cis/trans isomerase activity in HeLa cells. FACS analysis showed that DTM induced G0 arrest of the HCT116 cells. Our results suggest that DTM has the potential to guide the development of novel antifungal and/or anticancer drugs. (C) 2009 Elsevier Inc. All rights reserved.