Grant: Operating Grant

Anticancer drugs that target DNA topoisomerase enzymes are the most effective and widely prescribed anticancer drugs in current use. More than half of all current cancer chemotherapy treatments use topoisomerase II-targeted drugs. However, the currently used anticancer drugs have a number of properties that must be improved. The use of the widely used anthracycline class of anticancer drugs results causes a potentially fatal cardiotoxicity. The problem of serious cardiotoxic side effects appearing later in life is particularly acute for children treated with the anthracycline class of anticancer drugs for childhood leukemias which are highly curable. The goals of this project are to develop structurally novel potent anticancer drugs that target topoisomerase II that are not cardiotoxic. This goal will be achieved by using structure-based drug design to discover and synthesize new anticancer drugs that specifically target topoisomerase II at a newly characterized binding site on the enzyme. Molecular modeling and docking of candidate drugs into the topoisomerase II binding site and also its DNA substrate will be used to identify and develop new non-toxic anticancer drugs. Drugs discovered using these methods will be tested for their ability to kill various types of cancer cells. With the development of these new anticancer drugs the health of Canadians with cancer will benefit with higher cure rates and an improved quality of life.