title: Barbituric acid derivative BAS 02104951 inhibits PKCε, PKCη, PKCε/RACK2 interaction, Elk-1 phosphorylation in HeLa and PKCε and η translocation in PC3 cells following TPA-induction.
abstract: Protein kinase C (PKC) is a family of at least 10 isozymes involved in the activation of different signal transduction pathways. The exact function of these isozymes is not known at present. Isozyme-selective inhibitors would be important to explain the function of the different PKCs and are anticipated to have pharmaceutical potential. Here we report that the small organic molecule BAS 02104951 [5-(1,3-benzodioxol-5-ylmethylene)-1-(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrion], a barbituric acid derivative, inhibited PKCη and PKCε in vitro (IC(50) 18 and 36 µM, respectively). BAS 02104951 also inhibited the interaction of PKCε with its adaptor protein receptor for activated C-kinase 2 (RACK2) (IC(50) 28.5 µM). BAS 02104951 also inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Elk-1 phosphorylation in HeLa cells, translocation of PKCε and PKCη to the membrane following treatment of PC3 cells with TPA. The compound did not inhibit the proliferation of PC3 and HeLa cells. BAS 02104951 can be used as selective inhibitor of PKCε in cells not expressing PKCη and may serve as a basis for the rational development of a selective inhibitor of PKCε or PKCη, or for an inhibitor of the PKCε/RACK2 interaction.
authors.affiliation: Biocenter, Division of Medical Biochemistry, Innsbruck Medical University and Institute of Pharmacy, University of Innsbruck, Fritz-Pregl-Strasse 3, Innsbruck, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Gruber
authors.forename: Florian
authors.initials: F
authors.lastname: Rechfeld
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Nina
authors.initials: N
authors.lastname: Hauser
authors.forename: Markus
authors.initials: M
authors.lastname: Boehler
authors.forename: Dorota
authors.initials: D
authors.lastname: Garczarczyk
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
authors.forename: Johann
authors.initials: J
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D001463:Barbiturates / Q000737:chemistry*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D001463:Barbiturates; D004791:Enzyme Inhibitors; D050807:ets-Domain Protein Elk-1; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D013755:Tetradecanoylphorbol Acetate; C032232:barbituric acid