title: Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B.
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 GSK3beta phosphorylation in cellular assays, consistent with inhibition of PKB kinase activity in cells.
authors.affiliation: Cancer Research, UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey. Ian.Collins@icr.ac.uk
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: John
authors.initials: J
authors.lastname: Caldwell
authors.forename: Tatiana
authors.initials: T
authors.lastname: Fonseca
authors.forename: Alastair
authors.initials: A
authors.lastname: Donald
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.forename: Lisa-Jane K
authors.initials: LJ
authors.lastname: Hunter
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.forename: Martin G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Davies
authors.forename: Valerio
authors.initials: V
authors.lastname: Berdini
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Woodhead
authors.forename: Deborah
authors.initials: D
authors.lastname: Davis
authors.forename: Lisa C A
authors.initials: LC
authors.lastname: Seavers
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
mesh_terms: 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*
chemical_list: 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