HTS FOR DRUG LEADS TARGETING THE MAMMALIAN SELENOPROTEIN THIOREDOXIN REDUCTASE 1

针对哺乳动物硒蛋白硫氧还蛋白还原酶 1 的先导药物的 HTS

• 批准号: 8111122
• 负责人: Elias S.J. Arner
• 金额: $ 2.48万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111122
• 关键词: Adverse effects; Antineoplastic Agents; Antioxidants; Arsenic Trioxide; Biochemical; Biological; Biological Assay; Cancer cell line; Cell physiology; Cells; Chemicals; Chlorambucil; Cisplatin; Clinical; Collection; Data; Disease; Drug Delivery Systems; Enzymes; Evaluation; Exhibits; Fluorescence; Future; Genes; Genomics; Glutathione Reductase; Goals; Gold Compounds; In Vitro; Internet; Kinetics; Lead; Libraries; Malignant Neoplasms; Malignant neoplasm of testis; Melphalan; Modeling; Molecular Target; Mus; Nitrosourea Compounds; Oxidation-Reduction; Pharmaceutical Preparations; Pharmacotherapy; Quinones; Rattus; Research; Research Personnel; Research Project Grants; Role; Screening procedure; Selenium; Selenocysteine; Series; Side; Small Interfering RNA; Staging; Structure; Structure-Activity Relationship; Substrate Cycling; Synthesis Chemistry; System; Triage; United States National Institutes of Health; analog; anticancer treatment; base; cancer cell; cancer therapy; cancer type; cellular targeting; cytotoxicity; drug efficacy; enzyme model; high throughput screening; improved; in vivo; inhibitor/antagonist; interest; novel; public health relevance; research study; selenoprotein; success; therapy development; thioredoxin reductase; thioredoxin reductase 1; tumor xenograft

DESCRIPTION (provided by applicant): Cancer is a devastating disease where available drug therapies often have limited success and are associated with severe toxic side effects. Still, in some cases drug therapy against certain forms of cancer is highly successful, eg. cisplatin treatment against testicular cancer. The success of a given therapy in a given cancer depends upon a web of chemical and biological interactions, where one key factor is the need for targeting of the right molecular target in cancer cells with the most efficient drug(s), showing the least toxic side effects. Many drugs in current use have been employed for decades and there is an urgent need for the identification of new compounds targeting important anticancer molecules. In this project, the researchers wish to search for new compounds that interact with a previously known important drug target for anticancer therapy, the selenium-containing enzyme called thioredoxin reductase 1 (TrxR1). Cellular processes involving selenium and selenoproteins are thought to have a major impact on the development and therapy of cancer and TrxR1 seems to be particularly important in this setting. The enzyme is also known to be targeted by several anticancer agents already used in clinical therapy (eg. cisplatin, chlorambucil, melphalan, nitrosoureas, arsenic trioxide, antitumor quinone compounds and more). Mammalian TrxR1 is a highly reactive selenoprotein, which has major importance for the control of cellular redox systems and antioxidant defense. It is upregulated in many types of cancer and its reactive selenocysteine residue is a presumed direct target for many of the so called electrophilic agents used for anticancer treatment. One of the PI's of this application (Arnir) is an expert in studies of TrxR1 and of its role as an anticancer drug target whereas the other PI (Simeonov) is an expert in conducting high throughput screens (HTS) using libraries of many thousands of well-defined molecules at the NIH Chemical Genomics Center. Joining forces in this project, Arnir and Simeonov have specific aims of identifying novel compounds interacting with TrxR1 and subsequently assessing these as drug leads for new anticancer agents. PUBLIC HEALTH RELEVANCE: Cancer is a devastating disease where available drug therapies often have limited success and are associated with severe toxic side effects. Chemicals targeting the selenium-containing enzyme thioredoxin reductase are likely to serve as promising probes for novel anticancer drugs. Identifying such compounds is the main goal of this research project, which may, for reasons described in detail in the research plan, yield the discovery of compounds having optimal modes of action. This in turn could help improving anticancer efficacy while minimizing toxic side in such treatment.

描述（由申请人提供）：癌症是一种毁灭性的疾病，可用的药物治疗通常成功有限，并伴有严重的毒副作用。尽管如此，在某些情况下，药物治疗对某些形式的癌症是非常成功的，如。顺铂治疗睾丸癌给定癌症中给定疗法的成功取决于化学和生物相互作用的网络，其中一个关键因素是需要用最有效的药物靶向癌细胞中正确的分子靶标，显示出最小的毒副作用。目前使用的许多药物已经使用了几十年，迫切需要鉴定靶向重要抗癌分子的新化合物。 在这个项目中，研究人员希望寻找新的化合物，这些化合物与以前已知的抗癌治疗的重要药物靶点相互作用，即称为硫氧还蛋白还原酶1（TrxR1）的含硒酶。涉及硒和硒蛋白的细胞过程被认为对癌症的发展和治疗有重大影响，TrxR1似乎在这种情况下特别重要。该酶也被已知为已经用于临床治疗的几种抗癌药物的靶向（例如，顺铂、苯丁酸氮芥、美法仑、亚硝基脲、三氧化二砷、抗肿瘤醌化合物等）。哺乳动物TrxR1是一种高活性硒蛋白，对细胞氧化还原系统和抗氧化防御具有重要作用。它在许多类型的癌症中被上调，并且其反应性硒代半胱氨酸残基是许多用于抗癌治疗的所谓亲电子剂的假定直接靶标。本申请的PI之一（Arnir）是研究TrxR1及其作为抗癌药物靶标的专家，而另一个PI（Simeonov）是在NIH化学基因组学中心使用数千个明确定义的分子库进行高通量筛选（HTS）的专家。在这个项目中，Arnir和Simeonov的具体目标是鉴定与TrxR1相互作用的新型化合物，并随后评估这些化合物作为新抗癌药物的药物先导。 公共卫生相关性：癌症是一种毁灭性的疾病，可用的药物治疗通常具有有限的成功，并与严重的毒副作用有关。靶向含硒硫氧还蛋白还原酶的化学物质可能作为新型抗癌药物的有前途的探针。鉴定这些化合物是本研究项目的主要目标，由于研究计划中详细描述的原因，可能会发现具有最佳作用模式的化合物。这反过来可以帮助提高抗癌疗效，同时最大限度地减少这种治疗中的毒副作用。

项目成果

Inhibition of thioredoxin reductase 1 by porphyrins and other small molecules identified by a high-throughput screening assay.

• DOI: 10.1016/j.freeradbiomed.2011.01.020
• 发表时间: 2011-05-01
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Prast-Nielsen, Stefanie;Dexheimer, Thomas S.;Schultz, Lena;Stafford, William C.;Cheng, Qing;Xu, Jianqiang;Jadhav, Ajit;Arner, Elias S. J.;Simeonov, Anton
• 通讯作者: Simeonov, Anton