抑制Hdm2和泛素活化酶:靶向泛素偶联系统在癌症中的作用。

A M Weissman, Y Yang, J Kitagaki, C A Sasiela, J A Beutler, B R O'Keefe
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引用次数: 12

摘要

泛素偶联系统为癌症和其他疾病的潜在分子靶标提供了丰富的来源。一个非常有趣的靶标是无名指泛素连接酶(E3) Hdm2/Mdm2,它在癌症中经常过度表达,是肿瘤抑制因子p53的关键E3。对于50%表达野生型p53的肿瘤,抑制Hdm2的药物具有巨大的潜在临床应用价值。我们总结了通过高通量筛选确定的小分子和天然产物提取物来鉴定Hdm2 E3活性抑制剂的持续努力。采用酶和基于细胞的检测策略,我们已经确定了阻断Hdm2 E3活性的抑制剂,激活p53反应,优先杀死表达p53的细胞,并具有导致转化细胞不同程度死亡的能力。因此,通过体外实验筛选Hdm2泛素连接酶活性抑制剂是鉴定激活癌细胞p53诱导细胞凋亡分子的有力手段。我们还讨论了在这些筛选过程中发现的泛素活化酶(E1)抑制剂的潜力。E1抑制剂同样可以作为新疗法的基础。此外,它们代表了对泛素偶联系统提供新见解的独特工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibiting Hdm2 and ubiquitin-activating enzyme: targeting the ubiquitin conjugating system in cancer.

The ubiquitin conjugating system represents a rich source of potential molecular targets for cancer and other diseases. One target of great interest is the RING finger ubiquitin ligase (E3) Hdm2/Mdm2, which is frequently overexpressed in cancer and is a critical E3 for the tumor suppressor p53. For those 50% of tumors that express wild-type p53, agents that inhibit Hdm2 have great potential clinical utility. We summarize our ongoing efforts to identify inhibitors of Hdm2 E3 activity by high-throughput screening of both defined small molecules and natural product extracts. Employing a strategy using both enzymatic and cell-based assays, we have identified inhibitors that block the E3 activity of Hdm2, activate a p53 response, preferentially kill p53-expressing cells, and have the capacity to differentially cause death of transformed cells. Therefore, screening for inhibitors of Hdm2 ubiquitin ligase activity through in vitro assays represents a powerful means of identifying molecules that activate p53 in cancer cells to induce apoptosis. We also discuss the potential of inhibitors of ubiquitin-activating enzyme (E1) that were discovered during these screens. E1 inhibitors may similarly serve as the basis for novel therapeutics. Additionally, they represent unique tools for providing new insights into the ubiquitin conjugating system.

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