Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.
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DOI：
10.1038/nature13393
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发表时间：
2014-07-31
期刊：
影响因子：
64.8
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
--
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
肿瘤癌基因包括转录因子，这些转录因子利用一般的转录机制维持致癌状态，但到目前为止，直接药物抑制转录因子被证明是困难的。然而，转录机制包含各种酶辅助因子，可以作为开发新的候选治疗药物的靶点，包括细胞周期蛋白依赖性激酶(CDK)。在这里，我们介绍了第一个共价CDK7抑制剂THZ1的发现和表征，它具有前所未有的能力靶向位于规范激酶域之外的远程半胱氨酸残基，为实现CDK7的选择性提供了一种意想不到的手段。癌细胞系图谱显示，包括T-ALL在内的部分癌细胞系对THZ1表现出特殊的敏感性。Jurkat T-ALL的全基因组分析表明，THZ1不成比例地影响RUNX1的转录，并暗示对THZ1的敏感性可能是由于RUNX1超级增强子赋予的脆弱性以及该转录因子在这些肿瘤细胞的核心转录调控电路中的关键作用。因此，CDK7激酶活性的药理学调节可能提供一种识别和治疗肿瘤类型的方法，这些肿瘤类型表现出对转录的极端依赖，以维持致癌状态。
Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has thus far proven difficult. However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of the first 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 T-ALL, exhibit exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL 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 this transcription factor’s key role in the core transcriptional regulatory circuitry of these tumor cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state.
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影响因子：
10.5
作者：
Shi J;Whyte WA;Zepeda-Mendoza CJ;Milazzo JP;Shen C;Roe JS;Minder JL;Mercan F;Wang E;Eckersley-Maslin MA;Campbell AE;Kawaoka S;Shareef S;Zhu Z;Kendall J;Muhar M;Haslinger C;Yu M;Roeder RG;Wigler MH;Blobel GA;Zuber J;Spector DL;Young RA;Vakoc CR
通讯作者：
Vakoc CR
影响因子：
16
作者：
Yamada, T;Yamaguchi, Y;Handa, H
通讯作者：
Handa, H
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
2.9
作者：
Patricelli, Matthew P.;Szardenings, A. Katrin;Kozarich, John W.
通讯作者：
Kozarich, John W.
影响因子：
64.5
作者：
FISHER, RP;MORGAN, DO
通讯作者：
MORGAN, DO