Grant: Operating Grant

Natural products have long been a source of innovative anticancer therapeutic agents. With respect to breast cancer, natural products and chemical derivatives of them constitute a large majority of clinically used chemotherapeutic agents. One class of natural products known as depsipeptides have been the focus of much attention in recent times for their capacity to kill breast cancer cells and act on targets that would lead to less toxicity. Two of the targets of depsipeptide natural products, BclXl and GRP78, are known to be upregulated in breast cancer cells leading to cancer cells ability to resist programmed cell death (apoptosis). The focus of this grant is to harness, and strategically re-engineer, the natural biosynthetic enzymes for making anticancer depsipeptides to create improved chemical analogs for breast cancer therapeutic development. We have designed a strategy to combine structural features of distinct anticancer depsipeptides to make possible new chemotherapeutic agents that have a much greater capacity to kill breast cancer cells.