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

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 PKC eta and PKC epsilon in vitro (IC50 18 and 36 mu M, respectively). BAS 02104951 also inhibited the interaction of PKC epsilon with its adaptor protein receptor for activated C-kinase 2 (RACK2) (IC50 28.5 mu M). BAS 02104951 also inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Elk-1 phosphorylation in HeLa cells, translocation of PKC epsilon and PKC eta 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 PKC epsilon in cells not expressing PKC eta and may serve as a basis for the rational development of a selective inhibitor of PKC epsilon or PKC eta, or for an inhibitor of the PKC epsilon/RACK2 interaction.