Submitted Abstract
K-ras is highly mutated in >20% of cancers and a driver of cancer cell stemness. However, currently no approved drug against K-ras exists. PDE6D (or PDEdelta) is a trafficking chaperone of prenylated proteins and has been nominated as a surrogate target for K-Ras. The first three generations of PDE6D inhibitors suffered from deficits that we addressed in completely new designed inhibitors. Our inhibitors, called Deltaflexins, feature a chemical spring and a cell penetration group, which allowed us to arrive at 1 micromolar cellular potency in the first generation. Our model compound, Deltaflexin1, selectively disrupts K-Ras, but not H-Ras membrane organization. This selectivity profile is reflected in its ability to block stemness traits of breast cancer cells. However, our data suggest that PDE6D itself and/ or its other clients can inhibit cancer cell stemness irrespective of the Ras mutation status. We will here focus on INPP5E as additional PDE6D client that is important for primary cilium function. The primary cilium is an important organelle involved in cell polarization and stemness signaling also in cancer cells.We therefore here propose a 3+1 year PhD project, to: 1.Determine the cellular on-target effect of Deltaflexins and their K-ras inhibitory activity. 2.Determine the effect of Deltaflexins on the recruitment of INPP5E to primary cilia, and on proper ciliary function. The second objective will be carried out in collaboration with Dr. Ismail from the CRUK Beatson Institute, an expert in PDE6D and ciliary biology. We expect an exciting PhD training, with top scientific interactions, contacts with pharma/biotech companies and high quality, open access publications. Moreover, this project will significantly advance the validation of PDE6D as a cancer-drug target.