title: Inhibitor hijacking of Akt activation.
abstract: The kinase Akt plays a central role as a regulator of multiple growth factor input signals, thus making it an attractive anticancer drug target. A-443654 is an ATP-competitive Akt inhibitor. Unexpectedly, treatment of cells with A-443654 causes paradoxical hyperphosphorylation of Akt at its two regulatory sites (Thr308 and Ser473). We explored whether inhibitor-induced hyperphosphorylation of Akt by A-443654 is a consequence of disrupted feedback regulation at a pathway level or whether it is a direct consequence of inhibitor binding to the ATP binding site of Akt. Catalytically inactive mutants of Akt revealed that binding of an inhibitor to the ATP site of Akt is sufficient to directly cause hyperphosphorylation of the kinase in the absence of any pathway feedback effects. We conclude that ATP-competitive Akt inhibitors impart regulatory phosphorylation of their target kinase Akt. These results provide new insights into both natural regulation of Akt activation and Akt inhibitors entering the clinic.
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuzumi
authors.forename: Dorothea
authors.initials: D
authors.lastname: Fiedler
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Gray
authors.forename: Brian
authors.initials: B
authors.lastname: Aizenstein
authors.forename: Randy
authors.initials: R
authors.lastname: Hoffman
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D055808:Drug Discovery; D004789:Enzyme Activation; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C504035:A 443654; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt