A small molecule-kinase interaction map for clinical kinase inhibitors
A small molecule-kinase interaction map for clinical kinase inhibitors
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DOI：
10.1038/nbt1068
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发表时间：
2005-03-01
影响因子：
46.9
通讯作者：
Lockhart, DJ
中科院分区：
文献类型：
--
作者：
Fabian, MA;Biggs, WH;Lockhart, DJ
激酶抑制剂作为一类新的治疗药物显示出巨大的前景。在这里，我们描述了一种有效的方法来确定激酶抑制剂的特异性，通过测量结合的小分子激酶的ATP位点。我们已经分析了20种激酶抑制剂，包括16种已批准的药物或临床开发中的药物，针对119种蛋白激酶。我们发现，特异性变化很大，并没有强烈的化学结构或预期目标的身份相关。许多新的相互作用被确定，包括紧密结合的p38抑制剂BIRB-796的伊马替尼耐药变异的ABL激酶，并结合伊马替尼的SRC家族激酶LICK。我们还表明，在吉非替尼反应患者中发现的表皮生长因子受体（EGFR）突变不影响吉非替尼或厄洛替尼的结合亲和力。我们的研究结果代表了一个系统的小分子-蛋白质相互作用地图的临床化合物在大量的相关蛋白质。
Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LICK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.