THZ1 | Potent and selective CDK7 inhibitor

THZ1 (1604810-83-4) is an irreversible, covalent inhibitor (dual ATP-site and allosteric covalent binding) of CDK7 (IC₅₀ = 15.6nM @ 20min and 3.2nM @ 180 min).¹ It displayed broad based antiproliferative activity with IC₅₀’s of less than 200nM against 53% of the 1000 cancer cell lines it was tested against. THZ1 disrupts transcription of several proteins including RUNX1, TAL1, and GATA3. It suppresses oncogenic transcription of MYCN-driven cancers.² THZ1 decreases STAT3 chromatin binding and expression of target genes such as MYC, PIM1, and others in peripheral T-Cell lymphoma cells with the Y640F STAT3 mutation.³ Addition of THZ1 to targeted cancer therapy increases cell death and hinders the development of drug-resistant cell populations in cellular and in vitro cancer models.⁴

References/Citations:

1) Kwiatkowski et al. (2014), Targeting transcription regulation in cancer with a covalent CDK7 inhibitor; Nature, 511 616
2) Chipumuro et al. (2014), CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription of MYCN-driven cancers; Cell , 159 1126
3) Cayrol et al. (2017), THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors; Nature Commun.,8 14290
4) Rusan et al. (2018), Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression; Cancer Discov., 8 59