title: Synthesis and evaluation of indazole based analog sensitive Akt inhibitors.
abstract: The kinase Akt is a key signaling node in regulating cellular growth and survival. It is implicated in cancer by mutation and its role in the downstream transmission of aberrant PI3K signaling. For these reasons, Akt has become an increasingly important target of drug development efforts and several inhibitors are now reaching clinical trials. Paradoxically it has been observed that active site kinase inhibitors of Akt lead to hyperphosphorylation of Akt itself. To investigate this phenomenon we here describe the application of a chemical genetics strategy that replaces native Akt with a mutant version containing an active site substitution that allows for the binding of an engineered inhibitor. This analog sensitive strategy allows for the selective inhibition of a single kinase. In order to create the inhibitor selective for the analog sensitive kinase, a diversity of synthetic approaches was required, finally resulting in the compound PrINZ, a 7-substituted version of the Abbott Labs Akt inhibitor A-443654.
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, MC 2280, San Francisco, California 94158, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okuzumi
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Ducker
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
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: D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008954:Models, Biological; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: C504035:A 443654; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt