Ricouart A, Gesquiere J C, Tartar A, Sergheraert C
Faculté de Pharmacie de Lille, URA CNRS 1309, Institut Pasteur de Lille, France.
J Med Chem. 1991 Jan;34(1):73-8. 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.
通过在同一结构中结合ATP结合位点和蛋白质底物的模拟物，设计出了一类新型的丝氨酸/苏氨酸蛋白激酶抑制剂。在所获得的几种强效拮抗剂中，活性最高的由异喹啉-5-磺酰胺（作为ATP模拟物）和Ser-Arg6（作为肽部分）组成，通过α-NH(CH2)2NH(CH2)2CO-连接子相连。该化合物对蛋白激酶C（PKC）的Ki为0.1微摩尔，对环磷酸腺苷依赖性蛋白激酶（PKA）的Ki为0.004微摩尔，其活性分别比市售抑制剂H-7高60倍和750倍。
