Exploring pyridine-based ligands against human vaccinia-related kinases 1 and 2

The human genome encodes two active vaccinia-related kinases, VRK1 and VRK2[1], that are involved in various cellular processes, such as cell replication, chromatin modification, and response to DNA damage [2].. However, no potent or selective VRK inhibitors are available to systematically investigate the cellular functions of these proteins and their therapeutic potential. Here, we report the design and synthesis of novel VRK ligands based on hybridization between the pyridine core from a MAP4K4 inhibitor and the difluorophenol moiety from the RSK inhibitor BI-D1870[3,4]. Co-crystal structures revealed that compounds bind to the ATP-binding site of the VRKs via polar interactions facilitated by the pyridine core and the difluorophenol moiety. For both proteins, compound binding is enthalpy driven (|ΔH| > |TΔS|). We expect our results to serve as starting points to the development of potent and selective ligands for VRK1/2.