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Phenylamino‐Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors of Protein Kinase C (PKC)
Author(s) -
Zimmermann Jürg,
Caravatti Giorgio,
Mett Helmut,
Meyer Thomas,
Müller Marcel,
Lydon Nicholas B.,
Fabbro Doriano
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290707
Subject(s) - chemistry , pyrimidine , protein kinase c , moiety , stereochemistry , threonine , serine , non competitive inhibition , tyrosine kinase , kinase , enzyme inhibitor , protein kinase a , enzyme , biochemistry , signal transduction
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 (IC 50 = 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.