Discovery of Novel PDEd Degraders for the Treatment of KRAS Mutant Colorectal Cancer

摘要

KRAS-PDE delta protein-protein interaction represents an appealing target for cancer therapy. However, fast release of high-affinity inhibitors from PDE delta hampered drug binding affinity and antiproliferative activity. To overcome the limitations, the first proteolysis-targeting chimeric (PROTAC) small molecules targeting PDE delta were designed. By employment of PDE delta inhibitor deltazinone (2) and cereblon ligand pomalidomide (6), a series of potent PROTAC PDE delta degraders were obtained. The most promising compound 17f efficiently induced PDE delta degradation and demonstrated significantly improved antiproliferative potency in KRAS mutant SW480 cells. Compound 17f also achieved significant tumor growth inhibition in the SW480 colorectal cancer xenograft model. This proof-of-concept study provided a new strategy to validate the druggability of KRAS-PDE delta interaction and offered an effective lead compound for the treatment of KRAS mutant cancer.