title: 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-alpha (IC50 = 0.79 microM) and not the other subtypes tested. The inhibition constants of PKC-alpha and the antiproliferative effect on T24 human bladder carcinoma cells showed a qualitative correlation, although with some exceptions.
authors.affiliation: CIBA Pharmaceuticals Division, Oncology and Virology Research Department, Ciba-Geigy Limited., Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Zimmermann
authors.forename: G
authors.initials: G
authors.lastname: Caravatti
authors.forename: H
authors.initials: H
authors.lastname: Mett
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: N B
authors.initials: NB
authors.lastname: Lydon
authors.forename: D
authors.initials: D
authors.lastname: Fabbro
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
chemical_list: D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011743:Pyrimidines; D011493:Protein Kinase C