INHIBITION OF SIGNAL-REGULATED PROTEIN-KINASES BY PLANT-DERIVED HYDROLYZABLE TANNINS

A variety of hydrolysable tannins purified from Phyllanthus amarus are potent inhibitors of rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK) with IC50 values (concentrations for 50% inhibition) in the range 0.2-1.7 mu M. The three most effective compounds of this series of hydrolysable tannins have five phenolic substituents. These three compounds are also the most effective inhibitors of wheat embryo Ca2+-dependent protein kinase (CDPK), rat brain Ca2+- and phospholipid-dependent protein kinase C (PKC) and Ca2+-calmodulin-dependent myosin light chain kinase (MLCK). The order of sensitivity for protein kinase inhibition by the hydrolysable tannins studied is cAK > CDPK > PKC > MLCK. Thus the IC50 values for protein kinase inhibition by the most potent compound are 0.2 mu M (for cAK), 1.8 mu M (for CDPK), 26 mu M (for PKC) and 56 mu M (for MLCK) when protein kinase affinity is measured using synthetic peptide substrates. These hydrolysable tannin inhibitors found are the most specific and potent plant-derived inhibitors of cAK yet found.