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THZ1

Cat. No. M5228
THZ1 Structure
Synonym:

CDK7 inhibitor

Size Price Availability Quantity
5mg USD 80  USD80 In stock
10mg USD 142  USD142 In stock
25mg USD 314  USD314 In stock
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Quality Control & Documentation
Biological Activity

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 5 and Ser 7, with concurrent loss of Ser 2 phosphorylation at 250 nM 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.

Product Citations
Protocol (for reference only)
Cell Experiment
Cell lines Jurkat, Loucy, KOPTK1 and DND-41 cell lines
Preparation method Cells are treated with THZ1, THZ1-R or dimethylsulphoxide (DMSO) for 0-6 h to assess the effect of time on the THZ1-mediated inhibition of RNAPII CTD phosphorylation. For subsequent experiments cells are treated with compounds for 4 h as determined by the time-course experiment described earlier, unless otherwise noted. For inhibitor washout experiments, cells are treated with THZ1, THZ1-R or DMSO for 4 h. Medium containing inhibitors is subsequently removed to effectively 'washout' the compound and the cells are allowed to grow in the absence of inhibitor. For each experiment, lysates are probed for RNAPII CTD phosphorylation and other specified proteins.
Concentrations 0-10 μM
Incubation time 4 h
Animal Experiment
Animal models Bioluminescent xenografted mouse model
Formulation 10% DMSO in D5W
Dosages 10 mg/kg
Administration i.v.
Chemical Information
Molecular Weight 566.05
Formula C31H28ClN7O2
CAS Number 1604810-83-4
Solubility (25°C) DMSO: ≥ 25 mg/mL
Storage Powder          -20°C   3 years ;  4°C   2 years
In solvent       -80°C   6 months ;  -20°C   1 month
Conversion of different model animals based on BSA (PMID: 27057123)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Nilson KA, et al. Mol Cell. THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing.

[2] Kwiatkowski N, et al. Nature. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.

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Keywords: THZ1, CDK7 inhibitor supplier, CDK, inhibitors, activators

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