Like a growing kid, rapidly growing tumor cells require significant energy, and this rapid growth can come with some unintended side effects. To protect themselves from the side effects of rapid growth, tumor cells rely on antioxidant proteins. Recent work has shown that this extra reliance on antioxidant proteins can be leveraged to sabotage tumor cell growth. 

One class of drugs that has seen a resurgence in cancer drug development are covalent inhibitors. These drugs form a bond with their target protein, disrupting protein function. Blockbuster covalent drugs such as the KRASG12C inhibitors Sotarasib and Adagrasib have shown significant clinical benefit to patients with aggressive cancers. 

New research from the lab of Brian Cunniff, PhD, led by graduate student Victoria Gibson and recently retired Research Analyst Terri Messier, and published in Science Advances looked to utilize the potential of covalent inhibitors to target the mitochondrial antioxidant protein, peroxiredoxin 3 (PRX3). Their findings indicate that targeting PRX3 with the new small molecule covalent inhibitors shows pre-clinical anti-cancer activity. In particular, the group found that a minimal fragment of the covalent inhibitor, Thiostrepton, is needed to maintain anticancer activity while minimizing alternative target interactions, indicating that targeting PRX3 with novel small molecule inhibitors is feasible. These results are in line with a previous clinical trial supported by the Cunniff lab which found that RSO-021, a PRX3 inhibitor, was both safe and showed early signs of efficacy.

This work sets the foundation for exploring additional clinically actionable compounds for the treatment of cancer. Increasing the number of drugs that can effectively treat cancer is an important step forward in mitigating resistance to therapy and improving patient outcomes. 

This work was supported by RS Oncology, a UVM Cancer Center Pilot Award, and was conducted in collaboration with Wake Forest University. 

You can read the full publication detailing this work here.