Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B.
Structure-based drug design of novel isoquinoline-5-sulfonamide inhibitors of PKB as potential antitumour agents was investigated. Constrained pyrrolidine analogues that mimicked the bound conformation of linear prototypes were identified and investigated by co-crystal structure determinations with the related protein PKA. Detailed variation in the binding modes between inhibitors with similar overall conformations was observed. Potent PKB inhibitors from this series inhibited GSK3beta phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells.
Collins
Ian
I
Cancer Research, UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey. Ian.Collins@icr.ac.uk
Caldwell
John
J
Fonseca
Tatiana
T
Donald
Alastair
A
Bavetsias
Vassilios
V
Hunter
Lisa-Jane K
LJ
Garrett
Michelle D
MD
Rowlands
Martin G
MG
Aherne
G Wynne
GW
Davies
Thomas G
TG
Berdini
Valerio
V
Woodhead
Steven J
SJ
Davis
Deborah
D
Seavers
Lisa C A
LC
Wyatt
Paul G
PG
Workman
Paul
P
McDonald
Edward
E
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D007546:Isoquinolines; D008024:Ligands; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C508673:isoquinoline-5-sulfonamide; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C039109:isoquinoline