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

• Published in: Journal of biochemistry (Tokyo) 2011-03, Vol.149 (3), p.331-336
• Main Authors: Gruber, Peter, Rechfeld, Florian, Kirchmair, Johannes, Hauser, Nina, Boehler, Markus, Garczarczyk, Dorota, Langer, Thierry, Hofmann, Johann
• Format: Article
• Language: English
• Subjects: Animals; Barbiturates - chemistry; Cell Line; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; ets-Domain Protein Elk-1 - metabolism; Fluorescent Antibody Technique; HeLa Cells; Humans; Phosphorylation - drug effects; Protein Binding - drug effects; Protein Kinase C - metabolism; Protein Kinase C-epsilon - metabolism; Rats; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/jb/mvq147

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 (IC₅₀ 18 and 36 μM, respectively). BAS 02104951 also inhibited the interaction of PKCε with its adaptor protein receptor for activated C-kinase 2 (RACK2) (IC₅₀ 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.