Phenylamino‐Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors of Protein Kinase C (PKC)

Abstract

Phenylamino-pyrimidines represent a novel class of inhibitors of the protein kinase C with a high degree of selectivity versus other serine/threonine and tyrosine kinases. Steady state kinetic analysis of N-(3-[1-imidazolyl]-phenyl)-4-(3-pyridyl)-2-pyrimidinamine (5), which showed potent inhibitory activity, revealed competitive kinetics relative to ATP. The adjacent H-bond acceptor of the pyrimidine moiety next to an H-bond donor of the phenylamine was found to be crucial for inhibitory activity. N-(3-Nitro-phenyl)-4-(3-pyridyl)-2-pyrimidinamine (7) preferentially inhibited PKC-α (IC₅₀ = 0.79 μM) and not the other subtypes tested. The inhibition constants of PKC-α and the antiproliferative effect on T24 human bladder carcinoma cells showed a qualitative correlation, although with some exceptions.