Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells
Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells
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DOI：
10.1038/leu.2010.233
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发表时间：
2011-01-01
期刊：
影响因子：
11.4
通讯作者：
Drewes, G.
中科院分区：
文献类型：
--
作者：
Kruse, U.;Pallasch, C. P.;Drewes, G.
药物诱导肿瘤性B细胞凋亡为慢性淋巴细胞白血病（CLL）的治疗提供了一条有前途的治疗途径。我们分析了一组临床多激酶抑制剂诱导原代CLL细胞凋亡的能力。靶向大量受体和细胞内酪氨酸激酶（包括c-KIT、FLT 3、BTK和SYK）的抑制剂相对无活性，而CDK抑制剂BMS-387032和flavopiridol显示出与星形孢菌素相似的显著疗效。使用kinobeads蛋白质组学方法，在CLL细胞中定量监测激酶表达谱和抑制剂与靶蛋白复合物的结合谱。受影响最大的靶点是CDK 9、细胞周期蛋白T1、AFF 3/4和MLLT 1，它们可能代表失调的正转录延伸因子（p-TEFb）复合物的四个亚基。尽管效力较低，但两种药物也结合含有CDK 7的基础转录因子BTF 2/TFIIH。星形孢菌素和格尔德霉素不影响这些靶点，因此似乎表现出不同的作用机制。这些数据支持p-TEFb抑制剂在CLL中的关键作用，支持其未来的临床开发。Leukemia（2011）25，89-100; doi：10.1038/leu.2010.233; 2010年10月14日在线发表
The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia (CLL). We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells. Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c-KIT, FLT3, BTK and SYK were comparatively inactive, the CDK inhibitors BMS-387032 and flavopiridol showed marked efficacy similar to staurosporine. Using the kinobeads proteomics method, kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells. The targets most potently affected were CDK9, cyclin T1, AFF3/4 and MLLT1, which may represent four subunits of a deregulated positive transcriptional elongation factor (p-TEFb) complex. Albeit with lower potency, both drugs also bound the basal transcription factor BTF2/TFIIH containing CDK7. Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development. Leukemia (2011) 25, 89-100; doi: 10.1038/leu.2010.233; published online 14 October 2010