Kruse C H, Holden K G, Offen P H, Pritchard M L, Feild J A, Rieman D J, Bender P E, Ferguson B, Greig R G, Poste G
Department of Medicinal Chemistry, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101.
J Med Chem. 1988 Sep;31(9):1768-72. doi: 10.1021/jm00117a016.
Tyrosine-specific protein kinases that transfer the terminal phosphate from ATP to protein acceptors are associated with certain transforming viruses and cell surface growth factor receptors. Here we describe the synthesis and testing of potential multisubstrate inhibitors of this class of enzymes. The inhibitors were prepared by covalent attachment of the terminal phosphate of ATP or its tetraphosphate analogue to tyrosine mimics. Testing against p60v-abl, the tyrosine kinase from the Abelson murine leukemia virus, showed that the series of inhibitors was moderately potent (IC50 values as low as 13 microM). However, structural modification of the tyrosine mimic, including replacement with a serine-like moiety, had little effect on potency. It is therefore concluded that the ATP moiety is largely responsible for binding and that the enzyme requires additional structural features for recognition of the tyrosine-containing substrate.
能将ATP末端磷酸基团转移至蛋白质受体的酪氨酸特异性蛋白激酶，与某些转化病毒及细胞表面生长因子受体有关。在此，我们描述了这类酶潜在多底物抑制剂的合成与测试。抑制剂是通过将ATP末端磷酸基团或其四磷酸类似物共价连接到酪氨酸模拟物上制备而成。针对来自Abelson小鼠白血病病毒的酪氨酸激酶p60v-abl进行测试，结果表明该系列抑制剂具有中等效力（IC50值低至13 microM）。然而，酪氨酸模拟物的结构修饰，包括用丝氨酸样部分取代，对效力影响不大。因此得出结论，ATP部分在很大程度上负责结合，并且该酶需要额外的结构特征来识别含酪氨酸的底物。
