Author/Authors :
Ian Collins، نويسنده , , John Caldwell، نويسنده , , Tatiana Fonseca، نويسنده , , Alastair Donald، نويسنده , , Vassilios Bavetsias، نويسنده , , Lisa-Jane K. Hunter، نويسنده , , Michelle D. Garrett، نويسنده , , Martin G. Rowlands، نويسنده , , G. Wynne Aherne، نويسنده , , Thomas G. Davies، نويسنده , , Valerio Berdini، نويسنده , , Steven J. Woodhead، نويسنده , , Deborah Davis Ascheim، نويسنده , , Lisa C.A. Seavers، نويسنده , , Paul، نويسنده ,
Abstract :
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 GSK3β phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells.
Keywords :
PKB , Cancer , Inhibitors , structure-based drug design
