Barbituric acid derivative BAS 02104951 inhibits PKC?, PKC?, PKC?/RACK2 interaction, Elk-1 phosphorylation in HeLa and PKC? and ? translocation in PC3 cells following TPA ...
- 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? and PKC? in vitro (IC(50) 18 and 36 µM, respectively). BAS 02104951 also inhibited the interaction of PKC? 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 PKC? and PKC? 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? in cells not expressing PKC? and may serve as a basis for the rational development of a selective inhibitor of PKC? or PKC?, or for an inhibitor of the PKC?/RACK2 interaction.
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