Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

• Published in: Nature (London) Vol. 511; no. 7511; pp. 616 - 620
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.07.2014; Nature Publishing Group
• Subjects: 38/61; 45/15; 59/5; 631/154/555; 631/67/1990/283; 631/67/395; 631/92/275; 82/58; 96/2; 96/31; 96/98; Analysis; Antineoplastic Agents - pharmacology; Cancer; Care and treatment; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Core Binding Factor Alpha 2 Subunit - metabolism; Crystal structure; Cyclin-Dependent Kinases - antagonists & inhibitors; Cysteine; Cysteine - metabolism; Enzyme Inhibitors - pharmacology; Experiments; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetic regulation; Genetic transcription; Health aspects; Humanities and Social Sciences; Humans; Jurkat Cells; Kinases; letter; Leukemia; multidisciplinary; Pharmacology; Phenylenediamines - pharmacology; Phosphorylation; Phosphorylation - drug effects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - enzymology; Pyrimidines - pharmacology; Regression analysis; Science; Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13393

Here, a covalent inhibitor targeting cyclin-dependent kinase 7 (CDK7) demonstrates in vitro and in vivo efficacy against T-cell acute lymphoblastic leukaemia by downregulating oncogenic transcriptional programs. CDK7 kinase as an anti-cancer target Pharmacological blockade of transcription is a possible means of targeting cancer cells. Direct pharmacological inhibition of transcription factors has proved problematic, so cyclin-dependent kinase (CDK) family members such as CDK7, which regulate transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II, could provide more druggable targets. Here Nathanael Gray and colleagues use a cell-based screen to identify a novel transcriptional inhibitor, THZ1, that covalently targets CDK7 and has anti-proliferative activity in human T-cell acute lymphoblastic leukaemia cell lines and in a xenograft mouse model. THZ1 is a phenylaminopyrimidine that uses a mechanism combining ATP-site and allosteric covalent binding as a means of attaining potency and selectivity for CDK7. Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state 1 , but direct pharmacological inhibition of transcription factors has so far proven difficult 2 . However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates 3 , including cyclin-dependent kinases (CDKs) 4 . 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.