Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

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(2). However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates', 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 RUNXI and suggests that sensitivity to THZ I may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNXI in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 Ifinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.