As tumours progress they accumulate mutations making them increasingly aggressive and resistant to therapies. Many of these mutations cripple the normal protective cellular mechanisms that halt cell growth and trigger the death of cells with damaged DNA. Reinstalling these protective pathways represents an attractive mechanism to sensitize some of the most aggressive cancer cells to treatment. One family of protective proteins lost or blocked by aggressive cancers are Cyclin Dependent Kinase Inhibitors (CKIs). Basic research and pharma development have led to synthetic CKIs, which have seen variable success in the clinic. One issue not considered by these drugs, is the existence of Speedy/Ringo, a family of proteins capable of overriding CKI activity. Spy1, a member of this family, is elevated in many aggressive cancers. Pre-clinical data in cells and animals supports our contention that developing drugs to block Spy1 function is a promising therapeutic approach.
This project will support an interdisciplinary team of researchers well positioned to make advances in developing compounds to block the mechanism of Spy1 through a rational drug design program. This project focuses on a critical step in that process, developing a high-throughput assay to screen for the most effective compounds in a cost- and time-effective manner.