HTS FOR DRUG LEADS TARGETING THE MAMMALIAN SELENOPROTEIN THIOREDOXIN REDUCTASE 1

描述(申请人提供)：癌症是一种毁灭性的疾病，现有的药物治疗往往效果有限，并与严重的毒副作用有关。尽管如此，在某些情况下，针对某些癌症的药物治疗是非常成功的，例如。顺铂治疗睾丸癌。一种特定疗法在特定癌症中的成功取决于一系列化学和生物相互作用，其中一个关键因素是需要用最有效的药物(S)在癌细胞中靶向正确的分子靶点，显示出最低的毒副作用。目前使用的许多药物已经使用了几十年，迫切需要识别针对重要抗癌分子的新化合物。在这个项目中，研究人员希望寻找与以前已知的抗癌治疗的重要药物靶点相互作用的新化合物，这种含硒酶称为硫氧还蛋白还原酶1(TrxR1)。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，而TrxR1在这一背景下似乎特别重要。这种酶也是已知的几种已经用于临床治疗的抗癌药物的靶点(例如。顺铂、百菌清、马法兰、亚硝脲、三氧化二砷、抗肿瘤醌化合物等)。哺乳动物TrxR1是一种高活性的硒蛋白，在细胞氧化还原系统的调控和抗氧化防御中具有重要作用。它在许多类型的癌症中上调，其反应性硒半胱氨酸残基被认为是许多用于抗癌治疗的所谓亲电剂的直接靶点。该应用程序的PI之一(Arnir)是研究TrxR1及其作为抗癌药物靶点的作用的专家，而另一位PI(Simeonov)是使用NIH化学基因组中心数千个明确定义的分子的文库进行高通量筛选(HTS)的专家。在这个项目中，Arnir和Simeonov联合起来，有明确的目标是识别与TrxR1相互作用的新化合物，并随后评估这些化合物作为新抗癌剂的药物先导。 公共卫生相关性：癌症是一种毁灭性的疾病，现有的药物治疗往往效果有限，并与严重的毒副作用有关。针对含硒酶硫氧还蛋白还原酶的化学物质很可能成为新型抗癌药物的有前途的探针。确定这类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，这可能会产生具有最佳作用模式的化合物的发现。这反过来又有助于提高抗癌效果，同时将此类治疗中的毒副作用降至最低。

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.