Identification of inhibitors of protein kinase B using fragment-based lead discovery

…, D Barford, R Downham, MD Garrett…

Index: Saxty, Gordon; Woodhead, Steven J.; Berdini, Valerio; Davies, Thomas G.; Verdonk, Marcel L.; Wyatt, Paul G.; Boyle, Robert G.; Barford, David; Downham, Robert; Garrett, Michelle D.; Carr, Robin A. Journal of Medicinal Chemistry, 2007 , vol. 50, # 10 p. 2293 - 2296

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Citation Number: 116

Abstract

Using fragment-based screening techniques, 5-methyl-4-phenyl-1 H-pyrazole (IC50 80 μM) was identified as a novel, low molecular weight inhibitor of protein kinase B (PKB). Herein we describe the rapid elaboration of highly potent and ligand efficient analogues using a fragment growing approach. Iterative structure-based design was supported by protein- ligand structure determinations using a PKA-PKB “chimera” and a final protein-ligand ...