Chemical Genetic and Biochmechical Studies of Mitotic Proteolysis

Harvard Medical School, Boston MA

Investigators

Linked publications, trials & patents

Abstract

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.