Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design.
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.
Donald
Alastair
A
McHardy
Tatiana
T
Rowlands
Martin G
MG
Hunter
Lisa-Jane K
LJ
Davies
Thomas G
TG
Berdini
Valerio
V
Boyle
Robert G
RG
Aherne
G Wynne
GW
Garrett
Michelle D
MD
Collins
Ian
I
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008024:Ligands; D011687:Purines; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases