Chemical Genetic and Biochmechical Studies of Mitotic Proteolysis

这个项目的目标是了解有丝分裂蛋白分解的功能和调控，通过 新型小分子缓蚀剂的开发与应用泛素-蛋白酶体途径发挥着 在所有真核细胞中通过有丝分裂调节进程的重要作用。受监管的关键 该途径的组成部分是一种泛素连接酶，称为后期促进复合体(ARC)。一旦这一次 连接酶泛素化其底物，它们是蛋白酶体降解的目标。我们已经确定了 阻断后期促进复合体泛素化能力小分子抑制剂 细胞提取液中的底物，以及抑制蛋白酶体底物通过 结合泛素链。在这项提案中，我们试图使用这些化合物来了解 依赖于APC的泛素化，目前仍知之甚少。此外，我们小组最近的工作 这表明APC使其底物泛素化为新型泛素链，因此我们希望 要了解这种形式的泛化的意义以及它如何影响底物对 蛋白酶体。最后，我们试图合成与泛素链结合的小分子的新版本，以 更好地了解这些分子是如何发挥作用的。总之，这些研究将为我们提供新的见解 APC泛素及其底物，以及泛化的底物如何被 蛋白酶体，以及提供新的化学工具，可能导致靶向药物的开发 这条重要的生化途径。 泛素-蛋白酶体系统调节许多影响疾病的基本过程，包括 神经退行性疾病，如阿尔茨海默氏症和帕金森氏症，以及多种形式的癌症。 最近，蛋白酶体的抑制剂已被批准用于治疗包括多发性肿瘤在内的多种癌症。 骨髓瘤。在这个项目中，我们试图使用和开发小分子抑制剂来阻断泛素蛋白酶体。 途径通过新的机制。最近的研究表明，后期促进作用 复合体可能在癌症中失控，因此找到新的方法来干扰其功能可能 导致治疗癌症的新型药物的发展。

The goal of this project is to understand the function and regulation of mitotic proteolysis through the development and application of novel small molecule inhibitors. The ubiquitin-proteasome pathway plays an essential role in regulating progression through mitosis in all eukaryotic cells. The critical regulated component of this pathway is a ubiquitin ligase termed the Anaphase-Promoting Complex (ARC). Once this ligase ubiquitinates its substrates, they are targeted for degradation by the proteasome. We have identified small molecule inhibitors that block that ability of the Anaphase-Promoting Complex to ubiquitinate its substrates in cell extracts, and also small molecules that inhibit the degradation of proteasome substrates by binding ubiquitin chains. In this proposal, we seek to use these compounds to understand the mechanism of APC-dependent ubiquitination, which remains poorly understood. Furthermore, recent work from our group suggests that the APC ubiquitinates its substrates with novel types of ubiquitin chains, and we therefore want to understand the significance of this form of ubiquitiantion and how it affects targeting of substrates to the proteasome. Finally, we seek to synthesize new versions of small molecules that bind to ubiquitin chains to better understand how these molecules function. Together these studies will provide new insights into how the APC ubiqutinates its substrates and how ubiquitianted substrates are targeted for degradation by the proteasome, as well as providing new chemical tools that may lead to the development of drugs that target this important biochemical pathway. The ubiquitin-proteasome system regulates many essential processes that impact on disease, including neurodegenerative diseases such as Alzheimer's and Parkinsons's disease, and also many forms of cancer. Recently, inhibitors of the proteasome have been approved for treatment of cancers including multiple myeloma. In this project, we seek to use and develop small molecule inhibitors that block the ubiquitinproteasome pathway through novel mechanisms. Recent work suggests that the Anaphase-Promoting Complex may be dysregulated in cancers, and thus finding new methods to interfere with its function may lead to the development of novel agents for the treatment of cancer.