Improve Radiation Therapy and Chemotherapy Effectiveness through Development of a New Class of Compounds that Target a Specific DNA Repair Pathway and Sensitize Tumors to Treatment in a Multitude of Human Malignancies
2017 Harrington Scholar-Innovator
Dr. Mahadevan and his team have identified Ku70/80, a protein that plays a pivotal role in the NHEJ process, as a potential therapeutic target in the pathway. What's more, using state-of-the-art, computer-based screens, they also have discovered a novel small molecule that interferes with this target and pathway.
As a Harrington Scholar-Innovator, Dr. Mahadevan hopes to connect with experts who can contribute to the rational design of small-molecule KU70/80 inhibitors, evaluate the molecule's activity in preclinical models and investigate its efficacy, safety, pharmacokinetic and pharmacodynamics properties in mouse models of cancer, including glioblastoma (brain cancer) and prostate cancer.
“We are working with structural biologists, medicinal chemists and radiobiologists to evaluate small-molecule inhibitors based on the original molecule (compound L). Currently we have generated 15 novel chemical entities and are testing these in a validated series of assays. Real progress has been made with compound improvement in activity, binding and solubility.”
“Crystallography is the next step, which will prove how the drug binds to the KU70/80 DNA-repair protein and may impact DNA binding to the protein. Once we have that information, we could be on to a winner.”
“In my practice as a clinical trials physician, I see cancer patients who have failed standard-of-care therapies and are seeking novel, first-in-class, investigational agents or combinations to prolong life and to help advance clinical research. Most of them are going to progress or die while on these trials, but my patients inspire me to find new treatments that will prolong life, as well as, provide for a good quality of life.”