THZ1 2HCl

Catalog No.S7549 Batch:S754903

Technical Data

Formula

C₃₁H₃₀Cl₃N₇O₂

Molecular Weight

638.97

CAS No.

2095433-94-4

Solubility (25°C)*

In vitro

DMSO

100 mg/mL (156.5 mM)

Water

Insoluble

Ethanol

Insoluble

In vivo (Add solvents to the product individually and in order)

Clear solution

5%DMSO 1 45%PEG300 2 50%ddH2O

4.0mg/ml

Taking the 1 mL working solution as an example, add 50 μL of 80 mg/ml clarified DMSO stock solution to 450 μL of PEG 300, mix evenly to clarify it; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description

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.

Targets

CDK7 ^[1]
(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 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^[1]. THZ1 causes defects in Pol II(polymerase II) phosphorylation, co-transcriptional capping, promoter proximal pausing, and productive elongation^[2].

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^[1].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines Jurkat, Loucy, KOPTK1 and DND-41 cell lines Concentrations 0-10 μM Incubation Time 4 h 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.
Animal Study:^{^[1]}	Animal Models Bioluminescent xenografted mouse model Dosages 10 mg/kg Administration i.v.

Cell Assay:^{^[1]}

Cell lines
Jurkat, Loucy, KOPTK1 and DND-41 cell lines
Concentrations
0-10 μM
Incubation Time
4 h
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.

Animal Study:^{^[1]}

Animal Models
Bioluminescent xenografted mouse model
Dosages
10 mg/kg
Administration
i.v.

References

Customer Product Validation

: Data from [Data independently produced by , , J Cancer, 2018, 9(17):3149-3155]

Selleck's THZ1 2HCl has been cited by 31 publications

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation [ Nat Commun, 2024, 15(1):2089]	PubMed: 38453961
CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties [ Signal Transduct Target Ther, 2023, 8(1):302]	PubMed: 37582812
Targeting transcriptional kinase of CDK7 halts proliferation of multiple myeloma cells by modulating the function of canonical NF-kB pathway and cell cycle regulatory proteins [ Transl Oncol, 2023, 35:101729]	PubMed: 37369156
Chemo-phosphoproteomic profiling with ATR inhibitors berzosertib and gartisertib uncovers new biomarkers and DNA damage response regulators [ bioRxiv, 2023, 10.1101/2023.04.03.535285]	PubMed: none
Rewiring of master transcription factor cistromes during high-grade serous ovarian cancer development [ bioRxiv, 2023, 2023.04.11.536378]	PubMed: 37090516
STREAMING-tag system reveals spatiotemporal relationships between transcriptional regulatory factors and transcriptional activity [ Nat Commun, 2022, 13(1):7672]	PubMed: 36539402
CDK7/12/13 inhibition targets an oscillating leukemia stem cell network and synergizes with venetoclax in acute myeloid leukemia [ EMBO Mol Med, 2022, e14990]	PubMed: 35253392
Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in Tcell acute lymphoblastic leukemia [ Haematologica, 2022, 10.3324/haematol.2022.280761]	PubMed: 36073513
Systematic illumination of druggable genes in cancer genomes [ Cell Rep, 2022, 38(8):110400]	PubMed: 35196490
Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer [ Breast Cancer Res, 2022, 24(1):41]	PubMed: 35715861

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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