Design of potent protein kinase inhibitors using the bisubstrate approach

• Published in: Journal of medicinal chemistry Vol. 34; no. 1; pp. 73 - 78
• Main Authors: RICOUART, A, GESQUIERE, J. C, TARTAR, A, SERGHERAERT, C
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 1991
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - metabolism; Binding Sites; Chemistry; Drug Design; Enzyme Inhibitors - chemical synthesis; Exact sciences and technology; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Kinetics; mimics; Molecular Structure; Organic chemistry; Peptides; Preparations and properties; Protein Kinase C - antagonists & inhibitors; protein kinase inhibitor; Protein Kinase Inhibitors; Structure-Activity Relationship; structure-activity relationships; Substrate Specificity; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamide; Nitrogen heterocycle; Enzyme inhibitor; Heptapeptide; Biological activity; Diamine; Ester; Structure activity relation; Kinase; Bicyclic compound; Bromine Organic compounds; Aromatic compound; Antagonist
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00105a012

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.