THZ1 is a covalent CDK7 inhibitor 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.
Storage Temp
Protected from light,Store at -20°C
Shipped In
Ice chest + Ice pads
Grade
Moligand™
Action Type
INHIBITOR
Mechanism of action
Inhibitor of cyclin dependent kinase 7
Product Description
Information
THZ1 is a covalentCDK7inhibitor 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.
Targets
CDK7 (Cell-based assay) 3.2 nM
In vitro
THZ1 uses a unique mechanism, combining ATP-site and allosteric covalent binding, as a means of attaining potency and selectivity for CDK7. THZ1 irreversibly inhibits RNAPII CTD phosphorylation by covalently targeting a unique cysteine located outside the kinase domain of CDK7. THZ1, but not THZ1-R, completely inhibits the phosphorylation of the established intracellular CDK7 substrate RNAPII CTD at Ser\u20095 and Ser\u20097, with concurrent loss of Ser\u20092 phosphorylation at 250\u2009nM in Jurkat cells. THZ1 exhibits strong antiproliferative effects across a broad range of cancer cell lines from various cancer types. In Jurkat cells, low-dose THZ1 has a profound effect on a small subset of genes, including the key regulator RUNX1, thus contributing to subsequent loss of the greater gene expression program and cell death. THZ1 causes defects in Pol II(polymerase II) phosphorylation, co-transcriptional capping, promoter proximal pausing, and productive elongation.
In vivo
THZ1 reduces the proliferation of KOPTK1 T-ALL cells in a human xenograft mouse model. THZ1 is well tolerated at 10 mg/kg with no observable body weight loss or behavioural changes, suggesting that it causes no overt toxicity in the animals.
Cell Research(from reference)
Cell lines：Jurkat, Loucy, KOPTK1 and DND-41 cell lines
1.Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, Tesar B et al.. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.. Nature, 511 (7511):(616-20). [PMID:25043025][10.1021/op500134e]
2.Liu F, Jiang W, Sui Y, Meng W, Hou L, Li T, Li M, Zhang L, Mo J, Wang J et al.. (2019) CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists.. Proc Natl Acad Sci USA, 116 (26):(12986-12995). [PMID:31182587][10.1021/op500134e]
3.Sun B, Mason S, Wilson RC, Hazard SE, Wang Y, Fang R, Wang Q, Yeh ES, Yang M, Roberts TM et al.. (2020) Inhibition of the transcriptional kinase CDK7 overcomes therapeutic resistance in HER2-positive breast cancers.. Oncogene, 39 (1):(50-63). [PMID:31462705][10.1021/op500134e]
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G2329586
