Design of potent protein kinase inhibitors using the bisubstrate approach.
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.
Ricouart
A
A
Faculté de Pharmacie de Lille, URA CNRS 1309, Institut Pasteur de Lille, France.
Gesquiere
J C
JC
Tartar
A
A
Sergheraert
C
C
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D015394:Molecular Structure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000255:Adenosine Triphosphate; D011493:Protein Kinase C