Identification of inhibitors of protein kinase B using fragment-based lead discovery.
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.
Saxty
Gordon
G
Woodhead
Steven J
SJ
Berdini
Valerio
V
Davies
Thomas G
TG
Verdonk
Marcel L
ML
Wyatt
Paul G
PG
Boyle
Robert G
RG
Barford
David
D
Downham
Robert
R
Garrett
Michelle D
MD
Carr
Robin A
RA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C520852:5-methyl-4-phenyl-1H-pyrazole; D000970:Antineoplastic Agents; D008024:Ligands; D011720:Pyrazoles; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases