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摘要 : 美国Dana-Farber癌症研究所等处的研究人员发现,转录抑制因子THZ1以共价键方式将CDK7作为目标,在人类T-细胞急性淋巴细胞性白血病细胞系中以及在一个异种移植小鼠模型中具有抗增殖活性。相关文章发表于2014年6月22日的《Nature》杂志上。


转录的药理阻断是定位癌细胞的一个可能手段。转录因子的直接药理抑制已被证明有问题,所以“依赖于细胞周期蛋白的激酶”(CDK)家族成员如 CDK7 (它们通过磷酸化“RNA聚合酶II”的羧基端域来调控转录)有可能提供更多的药物作用目标。

在这项研究中,Nathanael Gray及同事利用一个基于细胞的筛选方法识别出一个新的转录抑制因子,即THZ1,后者以共价键方式将CDK7作为目标,在人类T-细胞急性淋巴细胞性白血病细胞系中以及在一个异种移植小鼠模型中具有抗增殖活性。



Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Nicholas Kwiatkowski, Tinghu Zhang, Peter B. Rahl, Brian J. Abraham, Jessica Reddy,Scott B. Ficarro, Anahita Dastur, Arnaud Amzallag, Sridhar Ramaswamy, Bethany Tesar,Catherine E. Jenkins, Nancy M. Hannett, Douglas McMillin, Takaomi Sanda, Taebo Sim,Nam Doo Kim, Thomas Look, Constantine S. Mitsiades, Andrew P. Weng, Jennifer R. Brown, Cyril H. Benes, Jarrod A. Marto, Richard A. Young & Nathanael S. Gray

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.

对应Nature杂志: 2014年7月31日Nature杂志精选

来源: Nature 浏览次数:238


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