Using fragment-based screening techniques, 5-methyl-4-phenyl-1
H-pyrazole (IC
50 80
M) was identified as a novel, lowmolecular weight inhibitor of protein kinase B (PKB). Herein wedescribe the rapid elaboration of highly potent and ligand efficientanalogues using a fragment growing approach. Iterative structure-baseddesign was supported by protein-ligand structure determinations usinga PKA-PKB "chimera" and a final protein-ligand structure of a leadcompound in PKB
itself.