Grant: Operating Grant

Effective strategies to treat cancer patients rely on our ability to interfere with cellular processes that are deregulated in cancer cells. In recent years, abnormalities in protein turnover states are frequently observed in many types of cancer. In most cases, this can be attributed to the misbehaviour of a cellular machinery employing a small protein called ubiquitin, which attaches to target proteins and acts as a signal for their destruction. Therefore, ubiquitin ligases (that add ubiquitin to proteins) and deubiquitinases (that remove ubiquitin from proteins) have attracted increasing attention as novel targets for drug development. These enzymes are crucial mediators of key intracellular processes and manipulation of them will have profound impacts on protein activity, localization, and life span. Unfortunately, the lack of selective molecules to prevent functions of these enzymes, called inhibitors, has severely hampered attempts to manipulate them for therapeutic benefits. The goal of this project is to develop highly specific and potent inhibitors for oncogenic ubiquitin ligases and deubiquitinases. Using protein engineering technology, we propose to make ubiquitin-like molecules that will associate tightly with these enzymes in a manner that will block its catalytic function, and thus, act as inhibitors. We will validate their inhibitory function in cancer cell lines using established biological assays. Additional structural analyses of critical contacts that mediate specificity and affinity will further aid the design of chemical inhibitors. In conclusion, this work will generate invaluable tools to understand and modulate activity of ubiquitin ligases and deubiquitinases in human cancer cells and will shed light on effective cancer therapy.