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Nature DOI:10.1038/nature13393

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.

Publication TypeJournal Article
Year of Publication2014
AuthorsKwiatkowski, N, Zhang, T, Rahl, PB, Abraham, BJ, Reddy, J, Ficarro, SB, Dastur, A, Amzallag, A, Ramaswamy, S, Tesar, B, Jenkins, CE, Hannett, NM, McMillin, D, Sanda, T, Sim, T, Kim, NDoo, Look, T, Mitsiades, CS, Weng, AP, Brown, JR, Benes, CH, Marto, JA, Young, RA, Gray, NS
Date Published2014 Jul 31
KeywordsAntineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, Core Binding Factor Alpha 2 Subunit, Cyclin-Dependent Kinases, Cysteine, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Humans, Jurkat Cells, Phenylenediamines, Phosphorylation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Pyrimidines

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.


Alternate JournalNature
PubMed ID25043025
PubMed Central IDPMC4244910
Grant ListR01 CA130876-04 / CA / NCI NIH HHS / United States
U54 HG006097 / HG / NHGRI NIH HHS / United States
T32 GM008042 / GM / NIGMS NIH HHS / United States
R01 CA130876 / CA / NCI NIH HHS / United States
P01 NS047572-10 / NS / NINDS NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
R01 CA179483 / CA / NCI NIH HHS / United States
P01 NS047572 / NS / NINDS NIH HHS / United States
U54 HG006097-02 / HG / NHGRI NIH HHS / United States
R21 CA178860 / CA / NCI NIH HHS / United States
R01 HG002668 / HG / NHGRI NIH HHS / United States
HG002668 / HG / NHGRI NIH HHS / United States
CA178860-01 / CA / NCI NIH HHS / United States
CA109901 / CA / NCI NIH HHS / United States