Structure-based design of PDK1 inhibitors.

A macrocyclic 2-anilino-4-phenyl-pyrimidine CDK/Flt3/JAK2 inhibitor was found to have moderate PDK1 activity. After docking into a PDK1 X-ray structure it was suggested that the pyrimidine ring could be substituted for a purine thereby increasing the number of hydrophobic contacts with the protein and forming an additional hydrogen bond to the kinase hinge. Deletion of the macrocyclic linker allowed a more rapid optimisation of the aromatic substituents as well as the introduction of an amino-amide solubility tag. This improved both binding to the enzyme and physiochemical properties without compromising ligand efficiency.