THZ1 2HCl is a Cdk7 inhibitor (IC50s = 3.2-15.6 nM in vitro) that selectively targets a remote cysteine residue located outside of the classic kinase domain. THZ1 2HCl also targets Cdk12 kinase activity although at a higher concentration (IC50 = 250 nM).
CDK7, belonging to the CDK family, can form part of the TFIIH complex with Cyclin H/MAT1 and regulate RNA polymerase II transcription and DNA repair.[2] THZ1 is a highly selective inhibitor of CDK7 with IC50 value of 3.2nM (measured by THZ1 enzymatic activity). Treatment with THZ1≥250nM for 4h can completely inhibit the phosphorylation of the established intracellular RNAPII CTD, the substrate of CDK7, at Ser 5 and Ser 7 in Jurkat cells, with concurrent loss of Ser 2 phosphorylation. THZ1 on concentration of 250nM can reduced RNAPII occupancy genome wide at both promoters and gene bodies in while Flavopiridol reduced RNAPII density only across gene bodies. THZ1 showed broad-based activity with half-maximum inhibitory concentration (IC50) values less than 200nM against 598 cell lines, which have a strong enrichment of common expression of (proto-) oncogenic transcription factors involved in RNAPII-driven transcriptional regulation. Intravenous treatment of THZ1 10mg/kg once daily or twice days for 29 days exhibited efficacy in a human T-ALL cell-line KOPTK1 xenografted mouse model[1].
作用机制
THZ1 is a covalent CDK7 inhibitor which can target ATP-binding pocket of CDK7.[1]
(E/Z)-THZ1 dihydrochloride 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
Jurkat cells
Cytotoxicity assay
72 h
Cytotoxicity against human Jurkat cells assessed as cell viability after 72 hrs by resazurin assay, IC50=0.05 μM
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