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首页> 外文期刊>Biochemistry >Inhibition of protein kinase CK2 by condensed polyphenolic derivatives. An in vitro and in vivo study
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Inhibition of protein kinase CK2 by condensed polyphenolic derivatives. An in vitro and in vivo study

机译：缩合多酚衍生物对蛋白激酶CK2的抑制作用。体外和体内研究

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摘要

ATP site-directed inhibitors that can target individual kinases are powerful tools for use in signal transduction research, all the more so in the case of a pleiotropic, constitutively active protein kinase such as CK2, which is not turned on in response to specific stimuli. By screening a library of more than 200 derivatives of natural polyphenolic compounds, we have identified 16 molecules which inhibit CK2 with IC50 values of less than or equal to 1 muM. They belong to the classes of anthraquinones (six compounds), xanthenones (two compounds), fluorenones (one compound), and coumarins (seven compounds), and their inhibitory potency correlates with the presence of nitro, amino, or halogen substituents at specific positions. Three of the most potent inhibitors, MNX (1,8-dihydroxy-4-nitroxanthen-9-one), NBC (8-hydroxy-4-methyl-9-nitrobenzo[g]chromen-2-one), and DBC (3,8-dibromo-7-hydroxy-4-methylchromen-2-one), whose IC50 values range between 0.13 and 0.36 muM, are quite specific toward CK2 within a panel of 33 protein kinases tested. Treatment of Jurkat cells with these compounds promotes inhibition of endogenous CK2 and induction of apoptosis. A correlation is observed between their efficacy as CK2 inhibitors (as judged from IC50 values) and their capacity to induce cell death (DC50 values). Mutations of the unique CK2alpha residues Val66 and/or IIe174 to alanine have a detrimental effect on inhibition by these compounds with 16-67-fold increases in IC50 values. The combined usage of these reagents can be exploited to gain information about cellular functions mediated by CK2.
机译：可以靶向单个激酶的ATP定点抑制剂是用于信号转导研究的强大工具，在多效，组成型活性蛋白激酶（如CK2）的情况下尤其如此，后者不能响应特定刺激而开启。通过筛选200多种天然多酚化合物衍生物的文库，我们鉴定出16种抑制CK2的分子，IC50值小于或等于1μM。它们属于蒽醌（六个化合物），黄酮（两个化合物），芴酮（一个化合物）和香豆素（七个化合物）的类别，它们的抑制能力与特定位置上硝基，氨基或卤素取代基的存在有关。 。三种最有效的抑制剂：MNX（1,8-二羟基-4-硝基氧杂蒽-9-one），NBC（8-羟基-4-甲基-9-硝基苯并[g]铬n-2-one）和DBC（ 3,8-dibromo-7-hydroxy-4-methylchromen-2-one）（IC50值介于0.13和0.36μM之间）对一组测试的33种蛋白激酶中的CK2具有非常高的特异性。用这些化合物处理Jurkat细胞可促进内源性CK2的抑制和凋亡的诱导。观察到它们作为CK2抑制剂的功效（根据IC50值判断）与诱导细胞死亡的能力（DC50值）之间存在相关性。独特的CK2alpha残基Val66和/或IIe174突变为丙氨酸对这些化合物的抑制作用具有有害作用，IC50值增加16-67倍。这些试剂的组合用法可用于获得有关CK2介导的细胞功能的信息。

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