National Center for
2C1B: Structure of cAMP-dependent protein kinase complexed with (4R,2S)-5'-(4-(4-Chlorobenzyloxy)pyrrolidin-2-ylmethanesulfonyl)isoquinoline
Bioorg. Med. Chem. (2006) 14 p.1255-1273
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.