Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib, reveal novel kinase and nonkinase targets
Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib, reveal novel kinase and nonkinase targets
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DOI：
10.1182/blood-2007-07-102061
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发表时间：
2007-12-01
期刊：
影响因子：
20.3
通讯作者：
Superti-Furga, Giulio
中科院分区：
文献类型：
--
作者：
Rix, Uwe;Hantschel, Oliver;Superti-Furga, Giulio
Bcr-abl酪氨酸激酶抑制剂伊马替尼代表了目前慢性粒细胞白血病的一线治疗。由于许多患者对伊马替尼产生耐药性，两种第二代药物尼洛替尼和达沙替尼被开发出来，显示出对bcr-abl的增强效力。为了预测潜在的副作用和新的医疗用途，我们通过化学蛋白质组学为所有3种药物生成了全面的药物-蛋白质相互作用图谱。我们的研究得到了四个主要发现：(1)3种药物的相互作用曲线显示出很大的差异，只有很小的重叠覆盖了ABL激酶。(2)Dasatinib结合了30多个Tyr和Ser/Thr激酶，包括免疫系统的主要调节因子，提示Dasatinib可能对免疫功能有特殊影响。(3)尽管尼洛替尼具有很高的特异性，但受体酪氨酸激酶DDR1被确认为另一个主要靶点。(4)在生理浓度下，氧化还原酶NQO(2)被伊马替尼和尼洛替尼结合并抑制，这是这两种药物的第一个非激酶靶点。
The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia. Because many patients develop imatinib resistance, 2 second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed. To predict potential side effects and novel medical uses, we generated comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs. Our studies yielded 4 major findings: (1) The interaction profiles of the 3 drugs displayed strong differences and only a small overlap covering the ABL kinases. (2) Dasatinib bound in excess of 30 Tyr and Ser/Thr kinases, including major regulators of the immune system, suggesting that dasatinib might have a particular impact on immune function. (3) Despite the high specificity of nilotinib, the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. (4) The oxidoreductase NQO(2) was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs.