Specific Inhibition of Cyclic AMP-Dependent Protein Kinase by the Antimalarial Halofantrine and by Related Phenanthrenes

The phenanthrenemethanol antimalarial halofantrine is a potent inhibitor of bovine heart and rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK) (IC50 values 2.1 μM and 0.6μM, respectively). The inhibition of rat liver cAK by halofantrine is non-competitive with respect to both ATP and to the synthetic peptide substrate employed (LRRASLG). Halofantrine is a poor inhibitor of calmodulin-dependent myosin light chain kinase (MLCK) and wheat embryo Ca2+-dependent protein kinase (CDPK) and does not inhibit rat brain Ca2+- and phospholipid-dependent protein kinase C (PKC). In contrast, the acridine-based antimalarial quinacrine and a variety of quinoline-based antimalarials are very poor inhibitors of cAK, the best inhibitor being chloroquine (IC50 for bovine heart cAK, 80 μM). Quinacrine and the quinoline-based antimalarials variously inhibit CDPK, PKC and MLCK albeit at relatively high concentrations (about 1 to 4x10-4m), the best inhibitors found being primaquine, pentaquine and mefloquine (IC50 values for MLCK 49, 103 and 33 μM, respectively). A number of phenanthrene derivatives having a 9-hydroxy or 9-keto substituent, namely phenanthrenequinone, 6(5 H)-phenanthridinone and 9-phenanthrol are potent inhibitors of bovine heart cAK (IC50 values 8, 10 and 10 μM, respectively) and of MLCK (IC50 values 6,53 and 10 μM, respectively). The selective, high affinity interaction of halofantrine with cAK may contribute to biological effects in vivo of this clinically-employed antimalarial compound.