Grant: Canada Postdoctoral Research Award (CPRA) program

Background: Cancer is the leading cause of death in Canada, and current treatments often fail to fully control tumors or help the immune system fight back. A key problem is an enzyme called DGK alpha, which helps cancer cells grow and survive while shutting down immune cells that normally attack tumors. Blocking DGK alpha is a promising way to both slow cancer growth and restore immune function. However, existing drugs that target DGK alpha are not precise, break down too quickly, and may cause unwanted side effects. Hypothesis: We believe that designing new, highly selective DGK alpha inhibitors will stop cancer-promoting activity and re-activate the body's natural immune defenses. Objectives: Design and identify new small-molecule DGK alpha inhibitors using artificial intelligence (AI) and structural modeling. Test these new compounds to confirm their ability to block DGK alpha and restore immune function in human immune cells. Assess how stable, safe, and effective these compounds to identify the best candidates. Methods: We will use AI-powered drug design to generate thousands of potential inhibitors and select the best candidates based on strength, safety, and drug-like properties. Advanced computer modeling will predict how strongly the compounds bind to DGK alpha. The top candidates will be synthesized in the lab and tested for their ability to block DGK alpha activity, restore immune cell function, and remain stable in the body. Significance: This project will deliver "first-in-class" DGK alpha inhibitors that are safer, stronger, and longer-lasting than current options. For patients, this means new treatments that fight cancer by boosting the body's own immune defenses, with fewer side effects. At the population level, better therapies will reduce the burden of cancer, improve quality of life, and lower health system costs. This research lays the foundation for future clinical trials and advances precision medicine for Canadians.