The VRK2-KD co-structure also revealed that the 18 sulfonamide group pointed away from the protein ATP-binding site and was completely solvent-exposed. A similar observation was made for the difluorophenol group in 5 that did not interact with VRK1-KD αC (Supplementary Figure ). Our DSF results also indicated that placement of polar groups in the meta-position resulted in slight increases of ΔTm, specially for VRK2-KD (10 vs. 11, for example). At this position, polar groups from the ligand might be able to engage polar groups from VRK2-KD P-loop.