产品号 #73302_C
酪氨酸激酶抑制剂；抑制BCR/ABL和ABL
总览
Nilotinib是致癌酪氨酸激酶BCR-ABL的第二代抑制剂，对BCR-ABL野生型、E255K突变型和T315I突变型的IC50分别为19 nM、140 nM和9,200 nM（Kitagawa等；Verstovsek等；O’Hare）。它与ABL的ATP结合位点结合，亲和力高于imatinib（Manley 等；Verstovsek等）。在浓度低于1 μM时，它对盘状蛋白结构域受体DDR-1和DDR-2、血小板衍生生长因子受体PDGFR-α和PDGFR-β、干细胞因子受体（KIT）以及集落刺激因子1受体（CSF-1R，Manley等）也具有活性。
癌症研究
·抑制多种野生型和突变型费城染色体（Philadelphia chromosome）阳性急性淋巴细胞白血病（Ph+ ALL）和慢性粒细胞白血病（CML）细胞的增殖（Verstovsek等；O'Hare）。
·通过DNA解旋酶复合物、细胞周期蛋白和细胞周期蛋白依赖性激酶的转录变化，抑制人肺细胞系A549中的细胞增殖和S期进展（Ji等）。
细胞类型
癌细胞及细胞系，白血病/淋巴瘤细胞
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
研究领域
癌症
CAS 编号
641571-10-0
化学式
C₂₈H₂₂F₃N₇O
纯度
≥ 95 %
通路
酪氨酸激酶
靶点
ABL，BCR/ABL
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (2)
Publications (5)
Activity-based kinase profiling of approved tyrosine kinase inhibitors. Genes to cells : devoted to molecular & cellular mechanisms 2013
Abstract
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 K(m) for ATP. In addition, profiling at a physiological ATP concentration (1 mm) was carried out, and the IC(50) values of the inhibitors against each kinase were compared with the estimated plasma-free concentration (calculated from published pharmacokinetic parameters of plasma C(trough) and C(max) 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 K(m) and physiological ATP concentrations could be useful in characterizing the targets and off-targets of kinase inhibitors.
Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochimica et biophysica acta 2010
Abstract
As a drug used to treat imatinib-resistant and -intolerant, chronic and advanced phase chronic myelogenous leukaemia, nilotinib is well characterised as a potent inhibitor of the Abl tyrosine kinase activity of wild-type and imatinib-resistant mutant forms of BCR-Abl. Here we review the profile of nilotinib as a protein kinase inhibitor. Although an ATP-competitive inhibitor of Abl, nilotinib binds to a catalytically inactive conformation (DFG-out) of the activation loop. As a consequence of this, nilotinib exhibits time-dependent inhibition of Abl kinase in enzymatic assays, which can be extrapolated to other targets to explain differences between biochemical activity and cellular assays. Although these differences confound assessment of kinase selectivity, as assessed using a combination of protein binding and transphosphorylation assays, together with cellular autophosporylation and proliferation assays, well established kinase targets of nilotinib in rank order of inhibitory potency are DDR-1textgreaterDDR-2textgreaterBCR-Abl (Abl)textgreaterPDGFRalpha/betatextgreaterKITtextgreaterCSF-1R. In addition nilotinib has now been found to bind to both MAPK11 (p38beta) and MAPK12 (p38alpha), as well as with very high affinity to ZAK kinase. Although neither enzymatic nor cellular data are yet available to substantiate the drug as an inhibitor of ZAK phosphorylation, modeling predicts that it binds in an ATP-competitive fashion.
Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities. PLoS computational biology 2009 SEP
Abstract
The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901) across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 641571-10-0 |
| Chemical Formula | C₂₈H₂₂F₃N₇O |
| Purity | ≥ 95% |
| Target | ABL, BCR/ABL |
| Pathway | Tyrosine Kinase |
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