Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design.
Alastair Donald, Tatiana McHardy, Martin G Rowlands, Lisa-Jane K Hunter, Thomas G Davies, Valerio Berdini, Robert G Boyle, G Wynne Aherne, Michelle D Garrett, Ian Collins
6-phenylpurines were identified as novel, ATP-competitive inhibitors of protein kinase B (PKB/Akt) from a fragment-based screen and were rapidly progressed to potent compounds using iterative protein-ligand crystallography with a PKA-PKB chimeric protein. An elaborated lead compound showed cell growth inhibition and effects on cellular signaling pathways characteristic of PKB inhibition.
