Kinase inhibitors: Not just for kinases anymore
Kinase inhibitors: Not just for kinases anymore
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DOI：
10.1021/jm020427b
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发表时间：
2003-04-10
影响因子：
7.3
通讯作者：
Shoichet, BK
中科院分区：
文献类型：
--
作者：
McGovern, SL;Shoichet, BK
激酶抑制剂被广泛用作生物试剂和药物设计的先导。它们的使用往往因缺乏特异性而变得复杂。虽然结合保守的ATP位点解释了它们的一些非特异性，但一些化合物抑制不知道结合ATP的蛋白质。已经发现，来自高通量筛选的混杂命中物可以充当聚集体。为了探索这种机制是否可以解释广泛使用的非特异性激酶抑制剂的作用，研究了15种此类化合物。其中八个，罗特勒，槲皮素，K-252 C，双吲哚马来酰亚胺I，双吲哚马来酰亚胺IX，U 0126，靛玉红，靛蓝，抑制三种不同的非激酶。抑制是时间依赖性的，对酶浓度敏感;通过光散射，化合物形成直径为100-1000 nm的颗粒。这些观察结果表明，这八种激酶抑制剂，至少在微摩尔浓度下，是混杂的，并作为聚集体。使用这些化合物在微摩尔或更高浓度下对单个酶的结果应谨慎解释。
Kinase inhibitors are widely employed as biological reagents and as leads for drug design. Their use is often complicated by their lack of specificity. Although binding conserved ATP sites accounts for some of their nonspecificity, some compounds inhibit proteins not known to bind ATP. It has been found that promiscuous hits from high-throughput screening may act as aggregates. To explore whether this mechanism might explain the action of widely used nonspecific kinase inhibitors, 15 such compounds were studied. Eight of these, rottlerin, quercetin, K-252c, bisindolylmaleimide I, bisindolylmaleimide IX, U0126, indirubin, and indigo, inhibited three diverse non-kinase enzymes. Inhibition was time-dependent and sensitive to enzyme concentration; by light scattering, the compounds formed particles of 100-1000 nm diameter. These observations suggest that these eight kinase inhibitors, at least at micromolar concentrations, are promiscuous and act as aggregates. Results obtained from the use of these compounds at micromolar or higher concentrations against individual enzymes should be interpreted cautiously.