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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Animals
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Binding Sites
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Biological Availability
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Chemistry, Pharmaceutical / methods*
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Chemistry, Physical / methods
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Crystallography, X-Ray / methods
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Drug Design
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Gene Deletion
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Humans
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Hydrogen Bonding
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Inhibitory Concentration 50
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Ligands
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Mice
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Microsomes, Liver / metabolism
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Models, Chemical
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Molecular Conformation
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrimidines / chemistry*
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Solubility
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Structure-Activity Relationship
Substances
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Ligands
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Protein Kinase Inhibitors
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Pyrimidines
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3-Phosphoinositide-Dependent Protein Kinases
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PDPK1 protein, human
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Pdpk1 protein, mouse
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Protein Serine-Threonine Kinases