Chemical Genetic and Biochmechical Studies of Mitotic Proteolysis

本项目的目的是通过蛋白质的表达来了解有丝分裂蛋白水解的功能和调节。 新型小分子抑制剂的开发和应用。泛素-蛋白酶体途径在 在所有真核细胞中通过有丝分裂调节进展的重要作用。关键监管 该途径的组分是称为后期促进复合物（ARC）的泛素连接酶。一旦这个 当连接酶泛素化其底物时，它们被蛋白酶体靶向降解。我们已经确定 阻断后期促进复合物泛素化其 细胞提取物中的底物，以及抑制蛋白酶体底物降解的小分子， 结合泛素链。在这个提议中，我们试图使用这些化合物来了解 APC依赖的泛素化，这仍然知之甚少。此外，我们小组最近的工作 表明APC用新型的泛素链泛素化其底物，因此我们希望 了解这种形式的泛素化的意义，以及它如何影响靶向底物， 蛋白酶体最后，我们试图合成新的小分子，结合到泛素链， 更好地了解这些分子的功能。这些研究将为我们提供新的见解， APC泛素化其底物以及泛素化的底物如何被APC降解。 蛋白酶体，以及提供新的化学工具，可能导致药物的发展， 这一重要的生化途径。 泛素-蛋白酶体系统调节许多影响疾病的重要过程，包括 神经退行性疾病，如阿尔茨海默病和帕金森病，以及许多形式的癌症。 最近，蛋白酶体抑制剂已被批准用于治疗癌症，包括多种癌症。 骨髓瘤在这个项目中，我们寻求使用和开发小分子抑制剂， 通过新的机制。最近的研究表明，后期促进 复合物可能在癌症中失调，因此找到新的方法来干扰其功能可能会 导致用于治疗癌症的新药剂的开发。

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.