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J Med Chem. 1991 Jan;34(1):73-8.

Design of potent protein kinase inhibitors using the bisubstrate approach.

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Faculté de Pharmacie de Lille, URA CNRS 1309, Institut Pasteur de Lille, France.


A new class of serine/threonine protein kinase inhibitors was designed by associating, in the same structure, mimics of both the ATP binding site and a protein substrate. Among the several potent antagonists which were obtained, the most active consists of isoquinoline-5-sulfonamide, as ATP mimic, and Ser-Arg6, as peptidic moiety, bound by a-NH(CH2)2NH(CH2)2CO-linker. This compound, with a Ki of 0.1 microM toward protein kinase C (PKC) and 0.004 microM toward cyclic AMP dependent protein kinase (PKA), is respectively 60- and 750-fold more active than the commercial inhibitor H-7.

[Indexed for MEDLINE]

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