Activity-based kinase profiling of approved tyrosine kinase inhibitors
Activity-based kinase profiling of approved tyrosine kinase inhibitors
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DOI：
10.1111/gtc.12022
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发表时间：
2013-02-01
期刊：
影响因子：
2.1
通讯作者：
Kirii, Yasuyuki
中科院分区：
文献类型：
--
作者：
Kitagawa, Daisuke;Yokota, Koichi;Kirii, Yasuyuki
使用大量人重组活性激酶，通过基于活性的激酶谱测定了9种获批酪氨酸激酶抑制剂（伊马替尼、达沙替尼、尼洛替尼、吉非替尼、厄洛替尼、拉帕替尼、索拉非尼、舒尼替尼和帕唑帕尼）的特异性。该组由79种酪氨酸激酶、199种丝氨酸/苏氨酸激酶、3种脂质激酶和29种疾病相关突变激酶组成。每种抑制剂的许多潜在靶点通过ATP Km处的激酶谱确定。此外，在生理ATP浓度（1 mm）下进行分析，并将抑制剂对每种激酶的IC 50值与估计的血浆游离浓度（根据已发表的血浆Ctrough和Cmax值的药代动力学参数计算）进行比较。该分析显示，批准的激酶抑制剂对其靶激酶进行了充分优化。这种分析也暗示了药物副作用中特定脱靶激酶的活性。因此，在Km和生理ATP浓度下的大规模激酶分析可用于表征激酶抑制剂的靶点和脱靶点。
The specificities of nine approved tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, and pazopanib) were determined by activity-based kinase profiling using a large panel of human recombinant active kinases. This panel consisted of 79 tyrosine kinases, 199 serine/threonine kinases, three lipid kinases, and 29 disease-relevant mutant kinases. Many potential targets of each inhibitor were identified by kinase profiling at the Km for ATP. In addition, profiling at a physiological ATP concentration (1 mm) was carried out, and the IC50 values of the inhibitors against each kinase were compared with the estimated plasma-free concentration (calculated from published pharmacokinetic parameters of plasma Ctrough and Cmax values). This analysis revealed that the approved kinase inhibitors were well optimized for their target kinases. This profiling also implicates activity at particular off-target kinases in drug side effects. Thus, large-scale kinase profiling at both Km and physiological ATP concentrations could be useful in characterizing the targets and off-targets of kinase inhibitors.