Chemical Information

Biological Activity of THZ1

THZ1 is a novel selective and potent covalent CDK7 inhibitor with IC50(binding affinity) of 3.2 nM; inhibits Jurkat cell's proliferation with IC50 of 50 nM.
IC50 value: 3.2 nM (Kd for CDK7)[1]
Target: CDK7
THZ1 has the unprecedented ability to target a remotecysteine 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 thatTHZ1 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 toidentify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.

References on THZ1

[1]. Nicholas Kwiatkowski, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature (2014) doi:10.1038/nature13393