Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

By Nicholas Kwiatkowski, Tinghu Zhang, P. Rahl, B. Abraham, J. Reddy, S. Ficarro, A. Dastur, A. Amzallag, Sridhar Ramaswamy, B. Tesar and 14 more. Nature, 2014

793 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fa112e3c1928c3ae7d7d807b4de923881720d978

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

dbSUPER: a database of super-enhancers in mouse and human genome (2015, background): “discovered that the transcription-targeting drug THZ1, a CDK7 inhibitor, preferentially reduced the expression of genes associated with super-enhancers (28).”
Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors (2020, methodology): “desthiobiotinylated compounds (Zhang et al., 2012; Kwiatkowski et al., 2014; Browne et al., 2018) (Fig.”
Transcriptional Addiction in Cancer (2017, positive): “…many different mechanisms (Figure 5A) (Chapuy et al., 2013; Chipumuro et al., 2014; Christensen et al., 2014; Drier et al., 2016; Hnisz et al., 2013; Kennedy et al., 2015; Kwiatkowski et al., 2014; Lin et al., 2016; Loven et al., 2013; Tomazou et al., 2015; Wang et al., 2015; Yang et al., 2015).”
An Oncogenic Super-Enhancer Formed Through Somatic Mutation of a Noncoding Intergenic Element (2014, methodology): “Drugs that target key components of the transcriptional machinery, such as BRD4 and CDK7 (12, 13, 17), have recently been shown to preferentially target tumor-specific super-enhancers, which provides a novel strategy to capitalize on these abnormalities for improved cancer therapy.”