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

Gordon Saxty; Steven J Woodhead; Valerio Berdini; Thomas G Davies; Marcel L Verdonk; Paul G Wyatt; Robert G Boyle; David Barford; Robert Downham; Michelle D Garrett; Robin A Carr

doi:10.1021/jm070091b

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

J Med Chem. 2007 May 17;50(10):2293-6. doi: 10.1021/jm070091b. Epub 2007 Apr 24.

Authors

Gordon Saxty, Steven J Woodhead, Valerio Berdini, Thomas G Davies, Marcel L Verdonk, Paul G Wyatt, Robert G Boyle, David Barford, Robert Downham, Michelle D Garrett, Robin A Carr

PMID: 17451234
DOI: 10.1021/jm070091b

Abstract

Using fragment-based screening techniques, 5-methyl-4-phenyl-1H-pyrazole (IC50 80 microM) 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 structure of a lead compound in PKBbeta itself.

MeSH terms

Adenosine Triphosphate / metabolism
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Binding Sites
Crystallography, X-Ray
Cyclic AMP-Dependent Protein Kinases / genetics
Ligands
Models, Molecular*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / chemistry*
Proto-Oncogene Proteins c-akt / genetics
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Stereoisomerism
Structure-Activity Relationship

Substances

5-methyl-4-phenyl-1H-pyrazole
Antineoplastic Agents
Ligands
Pyrazoles
Recombinant Fusion Proteins
Adenosine Triphosphate
Proto-Oncogene Proteins c-akt
Cyclic AMP-Dependent Protein Kinases