title: Structure-based design of PDK1 inhibitors.
abstract: 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.
authors: S BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore. anders@colours.dk
authors: Anders
authors: A
authors: Poulsen
authors: Stéphanie
authors: S
authors: Blanchard
authors: Chang Kai
authors: CK
authors: Soh
authors: Chaiping
authors: C
authors: Lee
authors: Meredith
authors: M
authors: Williams
authors: Haishan
authors: H
authors: Wang
authors: Brian
authors: B
authors: Dymock
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002627:Chemistry, Physical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D017353:Gene Deletion; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases