Kruse C H, Holden K G, Pritchard M L, Feild J A, Rieman D J, Greig R G, Poste G
Department of Medicinal Chemistry, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101.
J Med Chem. 1988 Sep;31(9):1762-7. doi: 10.1021/jm00117a015.
The synthesis and testing of potential multisubstrate inhibitors of tyrosine-specific protein kinases are described. One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-[4-(fluorosulfonyl)benzoyl]adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics. The resulting multisubstrate inhibitors were tested for their ability to inhibit the transfer of phosphate from ATP to a protein acceptor by p60v-abl, the tyrosine kinase encoded by the transforming gene (v-abl) of the Abelson murine leukemia virus (A-MuLV). Although the series of inhibitors displayed moderately potent activity (IC50 values as low as 19 microM), the absence of large effects produced by modification of the tyrosine mimic suggests that they do not behave as multisubstrate inhibitors but bind primarily through the adenosine moiety common to all the inhibitors. This interpretation is strengthened by the finding that the inhibitors lack specificity, inhibiting a serine kinase at comparable concentrations.
本文描述了酪氨酸特异性蛋白激酶潜在多底物抑制剂的合成与测试。其中一种底物ATP由已知的激酶抑制剂5'-[4-(氟磺酰基)苯甲酰基]腺苷模拟，该抑制剂通过磺酰基部分与酪氨酸模拟物共价连接。测试了所得多底物抑制剂抑制p60v-abl将磷酸从ATP转移至蛋白质受体的能力，p60v-abl是由Abelson小鼠白血病病毒（A-MuLV）的转化基因（v-abl）编码的酪氨酸激酶。尽管该系列抑制剂表现出中等强度的活性（IC50值低至19 microM），但酪氨酸模拟物修饰未产生显著影响，这表明它们并非作为多底物抑制剂发挥作用，而是主要通过所有抑制剂共有的腺苷部分结合。抑制剂缺乏特异性，在相当浓度下能抑制丝氨酸激酶，这一发现进一步支持了上述解释。
