Synthetic inhibitors of ubiquitin-binding cancer targets
Phase 2 (Round 1)
Our cells possess an elaborate mechanism to regulate the amount of proteins in cells, which allows them to remove damaged or nonfunctional proteins. This mechanism depends on a small protein called ubiquitin, which attaches to target proteins and signals their destruction. This process is critical if cells are to function normally. However, in many diseases, ubiquitin is not attached or removed as it should, resulting in abnormal protein degradation. Proper ubiquitin attachment or removal depends on specific enzymes that have recently become the focus of novel drug development, because they were shown to function aberrantly in several diseases. A few drugs are currently approved that affect these enzymes and have been successfully used to treat certain types of cancers, but they have undesirable side effects. Overall, there are few molecules that modulate the function of these enzymes, which has impeded attempts to manipulate them for therapeutic benefits.
Dr. Sachdev Sidhu of the University of Toronto is leading a team that will use an innovative high-throughput molecular genetics engineering platform, which is unique in the world and has attracted intense interest from industry and academia, to enable the rapid and cost-effective development of highly specific and potent ubiquitin-like molecules that attach to key, cancer-associated enzymes of the ubiquitin system, to block or enhance their function. The biological effect of these molecules will be validated in cell and animal models of cancer. The project will produce pre-clinical molecules ready for therapeutic development, and will enable the discovery of new drug targets, speed up drug development and generate effective anti-cancer drugs with fewer side effects, all of which should be of great socio-economic benefit to Canadians.