Drug resistance is a serious barrier to the treatment of breast cancer, leading to metastasis and cancer reoccurrences. Our project will generate the first preclinical drug that suppresses the ability of cancer cells to adapt to chemo- and immunotherapies. Clinical implementation of a drug stalling cancer evolution will be a major step in tackling drug resistance and cancer reoccurrences. Human cells contain an enzyme family called APOBEC3, which disables pathogens by hypermutating their DNA. However, breast cancer cells use APOBEC3-driven mutagenesis to increase rates of evolution enabling cancer cells to escape adaptive immune responses and resist drugs. APOBEC3 is not required for primary metabolism, and its inhibition offers a new strategy to augment existing therapies making them effective for much longer. This project will deliver the first APOBEC3 selective inhibitors working in live cells. These discoveries will be translated into new therapeutics.