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J. Biol. Chem., Vol. 266, Issue 24, 15771-15781, 08, 1991
D Toullec, P Pianetti, H Coste, P Bellevergue, T Grand-Perret, M Ajakane, V Baudet, P Boissin, E Boursier and F Loriolle
Staurosporine is the most potent inhibitor of protein kinase C (PKC)
described in the literature with a half-maximal inhibitory concentration
(IC50) of 10 nM. Nevertheless, this natural product is poorly selective
when assayed against other protein kinases. In order to obtain specific PKC
inhibitors, a series of bisindolylmaleimides has been synthesized.
Structure-activity relationship studies allowed the determination of the
substructure responsible for conferring high potency and lack of
selectivity in the staurosporine molecule. Several aminoalkyl
bisindolylmaleimides were found to be potent and selective PKC inhibitors
(IC50 values from 5 to 70 nM). Among these compounds GF 109203X has been
chosen for further studies aiming at the characterization of this chemical
family. GF 109203X was a competitive inhibitor with respect to ATP (Ki = 14
+/- 3 NM) and displayed high selectivity for PKC as compared to five
different protein kinases. We further determined the potency and
specificity of GF 109203X in two cellular models: human platelets and Swiss
3T3 fibroblasts. GF 109203X efficiently prevented PKC-mediated
phosphorylations of an Mr = 47,000 protein in platelets and of an Mr =
80,000 protein in Swiss 3T3 cells. In contrast, in the same models, the PKC
inhibitor failed to prevent PKC-independent phosphorylations. GF 109203X
inhibited collagen- and alpha-thrombin-induced platelet aggregation as well
as collagen- triggered ATP secretion. However, ADP-dependent reversible
aggregation was not modified. In Swiss 3T3 fibroblasts, GF 109203X reversed
the inhibition of epidermal growth factor binding induced by phorbol 12,13-
dibutyrate and prevented [3H] thymidine incorporation into DNA, only when
this was elicited by growth promoting agents which activate PKC. Our
results illustrate the potential of GF 109203X as a tool for studying the
involvement of PKC in signal transduction pathways.
The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C
Laboratoire de Biologie, Laboratoires Glaxo, Les Ulis, France.
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