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Chemical genomics screening of drugs modulating functions of telomere/telomerase

端粒/端粒酶功能调节药物的化学基因组学筛选

基本信息

批准号：
18390040
负责人：
MIZUKAMI Tamio
金额：
$ 8.75万
依托单位：
Nagahama Institute of Bio-Science and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390040/
关键词：
cancer protein drug reactivity telomere molecular target 蛋白質

项目摘要

In order to discover new telomerase inhibitors or new agents that act on telomere regulation mechanism which does not based on telomerase inhibition, we developed an unprecedented unique screening method with induction of shortened telomere as an activity indicator by a forward chemical approach using a yeast strain with shortened telomere length and found antimicrobial, anticancer compounds USC 1025A and chrolactomycin (TEY7) produced by microorganisms as active compounds. It was revealed that these compounds possess telomere-shortening-inducing activity as well as telomerase inhibitory activity within tumor cells but neither detailed mechanism of action nor direct target molecules are still unknown.The objectives of the study is to elucidate the mechanism of action of these compounds on the molecular level by identifying intracellular target molecules to which the compounds bind directly and to validate the possibility of the identified molecules as new molecular targets of anticancer agents by analyzing the function of the identified target molecules in telomere regulation and cancerous change of cells.In the study, we used biotin-labeled probes of UCS1025A and TEY7 and found the protein that binds to respective compound. As these labeled proteins are thought to contain a direct active site of the compounds, we made an analysis by in-gel protease digestion and mass spectrometry to identify binding protein.It can be expected that identification of the target molecules of these compounds and elucidation of their mechanisms of action will provide a new drug discovery approach that leads to development of new anticancer agents acting specifically on cancer cells with much less side effects compared to existing anticancer drugs.

为了发现新的端粒酶抑制剂或作用于端粒调节机制的新药物，而不是基于端粒酶抑制，我们通过正向化学方法，使用具有缩短的端粒长度的酵母菌株，开发了一种前所未有的独特的筛选方法，抗癌化合物USC 1025A和由微生物产生的色乳霉素（TEY 7）作为活性化合物。结果表明，这些化合物具有端粒缩短作用，本研究的目的是通过鉴定这些化合物直接结合的细胞内靶分子，在分子水平上阐明这些化合物的作用机制，并验证这些化合物在肿瘤细胞内的诱导活性以及端粒酶抑制活性，但无论是详细的作用机制还是直接的靶分子都是未知的，本研究的目的是通过鉴定这些化合物直接结合的细胞内靶分子，在分子水平上阐明这些化合物的作用机制，并验证这些化合物在肿瘤细胞内的诱导活性以及端粒酶抑制活性的可能性。通过分析已鉴定的靶分子在端粒调控和细胞癌变过程中的作用，确定了作为抗癌药物新的分子靶点的分子，在本研究中，我们使用生物素标记的探针UCS1025A和TEY 7，发现了与相应化合物结合的蛋白。由于这些标记的蛋白质被认为含有化合物的直接活性位点，我们做了一个分析，凝胶蛋白酶消化和质谱法鉴定结合蛋白。可以预期，这些化合物的靶分子的鉴定和其作用机制的阐明将提供一种新的药物发现方法，该方法导致开发特异性作用于癌细胞的新的抗癌剂，与现有的抗癌药物相比，副作用更小。