Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Title
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
Authors
Nicholas KwiatkowskiTinghu ZhangPeter B. RahlBrian J. AbrahamJessica ReddyScott B. FicarroAnahita DasturArnaud AmzallagSridhar RamaswamyBethany TesarCatherine E. JenkinsNancy M. HannettDouglas McMillinTakaomi Sanda심태보Nam Doo KimThomas LookConstantine S. MitsiadesAndrew P. WengJennifer R. BrownCyril H. BenesJarrod A. MartoRichard A. YoungNathanael S. Gray
Keywords
CDK7; RNA-POLYMERASE-II; ACTIVATING KINASE; SUPER-ENHANCERS; FACTOR TFIIH; CTD KINASE; PHOSPHORYLATION; ELONGATION; COMPLEX; IDENTIFICATION
Issue Date
2014-07
Publisher
Nature
Citation
VOL 511, NO 7511, 616-620
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/49133
ISSN
00280836
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KIST Publication > Article
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