HTS FOR DRUG LEADS TARGETING THE MAMMALIAN SELENOPROTEIN THIOREDOXIN REDUCTASE 1

描述（由申请人提供）：癌症是一种毁灭性的疾病，现有的药物治疗通常效果有限，并伴有严重的毒副作用。然而，在某些情况下，针对某些癌症的药物治疗是非常成功的。顺铂治疗睾丸癌。针对特定癌症的特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先前已知的抗癌治疗的重要药物靶点相互作用的新化合物，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，而TrxR1似乎在这种情况下尤为重要。这种酶也被一些已经在临床治疗中使用的抗癌药物所靶向。顺铂、氯苯、美法兰、亚硝基脲、三氧化二砷、抗肿瘤醌类化合物等)。哺乳动物TrxR1是一种高活性硒蛋白，对控制细胞氧化还原系统和抗氧化防御具有重要意义。它在许多类型的癌症中被上调，其活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标。该应用程序的一位PI （Arnir）是TrxR1研究及其作为抗癌药物靶点作用的专家，而另一位PI （Simeonov）是使用NIH化学基因组学中心数千个定义明确的分子文库进行高通量筛选（HTS）的专家。在这个项目中，Arnir和Simeonov的共同目标是确定与TrxR1相互作用的新化合物，并随后评估这些化合物作为新的抗癌药物的先导。

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.