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THZ1Covalent CDK7 inhibitor,potent and selective

THZ1

Catalog No. BCC4005
Size Price Stock
10mM (in 1mL DMSO) $100.00 In stock
5mg $80.00 In stock
10mg $150.00 In stock
25mg $300.00 In stock
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Quality Control of THZ1

Chemical structure

THZ1

Biological Activity of THZ1

Description THZ1 is an irreversible, potent and selective inhibitor of CDK7(cyclin-dependent kinase 7) with an IC50 value of 3.2 nM.
Targets CDK7          
IC50 3.2 nM          

Protocol

Cell experiment: [1]

Cell lines

Jurkat and Loucy T-ALL cell lines

Preparation method

The solubility of this compound in DMSO is <10 mm. general tips for obtaining a higher concentration: please warm the tube at 37 °c 10 minutes and>

Reacting condition

72 hours IC50: 50 nM (for Jurkat cells), 0.55 nM (for Loucy T-ALL cells)

Applications

As a CDK7 inhibitor, THZ1 potently inhibited proliferation of Jurkat and Loucy T-ALL cell lines with IC50 values of 50 nM and 0.55 nM, respectively.

Animal experiment: [1]

Animal models

Mice bearing KOPTK1 xenografts

Dosage form

10 mg/kg, twice daily for 29 days

Application

THZ1 exhibited efficacy in a bioluminescent xenografted mouse model using the human T-ALL cell-line KOPTK1 when dosed twice daily at 10mg/kg. THZ1waswell tolerated at these doseswith no observable body weight loss or behavioural changes, suggesting that it caused no overt toxicity in the animals.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Kwiatkowski N, Zhang T, Rahl P B, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature, 2014, 511(7511): 616-620.

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Chemical Properties of THZ1

Cas No. 1604810-83-4 SDF Download SDF
Chemical Name N-[3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]phenyl]-4-[[(E)-4-(dimethylamino)but-2-enoyl]amino]benzamide
SMILES CN(C)CC=CC(=O)NC1=CC=C(C=C1)C(=O)NC2=CC=CC(=C2)NC3=NC=C(C(=N3)C4=CNC5=CC=CC=C54)Cl
Standard InChIKey OBJNFLYHUXWUPF-IZZDOVSWSA-N
Standard InChI InChI=1S/C31H28ClN7O2/c1-39(2)16-6-11-28(40)35-21-14-12-20(13-15-21)30(41)36-22-7-5-8-23(17-22)37-31-34-19-26(32)29(38-31)25-18-33-27-10-4-3-9-24(25)27/h3-15,17-19,33H,16H2,1-2H3,(H,35,40)(H,36,41)(H,34,37,38)/b11-6+
Formula C31H28ClN7O2 M.Wt 566.05
Solubility Soluble in DMSO
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other courier with RT , or blue ice upon request.

Preparing Stock Solutions of THZ1

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7666 mL 8.8331 mL 17.6663 mL 35.3326 mL 44.1657 mL
5 mM 0.3533 mL 1.7666 mL 3.5333 mL 7.0665 mL 8.8331 mL
10 mM 0.1767 mL 0.8833 mL 1.7666 mL 3.5333 mL 4.4166 mL
50 mM 0.0353 mL 0.1767 mL 0.3533 mL 0.7067 mL 0.8833 mL
100 mM 0.0177 mL 0.0883 mL 0.1767 mL 0.3533 mL 0.4417 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Background on THZ1

THZ1 is a covalent inhibitor of CDK7 with IC50 value of 3.2nM [1].

THZ1 covalently modifies CDK7 by targeting C312 residue outside of the kinase domain, providing an unanticipated means of achieving covalent selectivity. THZ1 potently inhibits proliferation of Jurkat and Loucy T-ALL cell lines with IC50 values of 50nM and 0.55nM, respectively. In the kinase binding assay, THZ1 shows a good binding affinity with IC50 value of 3.2nM [1].

As an inhibitor of CDK7, THZ1 inhibits the phosphorylation of the C-terminal domain of RNAP polymerase II, effecting the regulation of transcription. THZ1 also inhibits the activation of the CDK proteins. It is reported to disrupt the CDK7 signalling pathways both in Jurkat cells and Loucy cells. THZ1 shows a broad-based activity with IC50 values less than 200nM in a variety of cancer cell lines. Among these cell lines, T-ALL is exceptional sensitivity to THZ1 due to the transcription effect of RUNX1 caused by THZ1 [1].

References:
[1] Nicholas Kwiatkowski, Tinghu Zhang, Peter B. Rahl et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature, 2014.

References on THZ1

Corrigendum: THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors.[Pubmed: 28218232]




THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors.[Pubmed: 28134252]


Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.

THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing.[Pubmed: 26257281]


The Cdk7 subunit of TFIIH phosphorylates RNA polymerase II (Pol II) during initiation, and, while recent studies show that inhibition of human Cdk7 negatively influences transcription, the mechanisms involved are unclear. Using in vitro transcription with nuclear extract, we demonstrate that THZ1, a covalent Cdk7 inhibitor, causes defects in Pol II phosphorylation, co-transcriptional capping, promoter proximal pausing, and productive elongation. THZ1 does not affect initiation but blocks essentially all Pol II large subunit C-terminal domain (CTD) phosphorylation. We found that guanylylation of nascent RNAs is length dependent and modulated by a THZ1-sensitive factor present in nuclear extract. THZ1 impacts pausing through a capping-independent block of DSIF and NELF loading. The P-TEFb-dependent transition into productive elongation was also inhibited by THZ1, likely due to loss of DSIF. Capping and pausing were also reduced in THZ1-treated cells. Our results provide mechanistic insights into THZ1 action and how Cdk7 broadly influences transcription and capping.

Kewords:

THZ1,1604810-83-4,Cell Cycle/Checkpoint,Cyclin-Dependent Kinases, supplier, inhibitor,Antagonist,Blocker,Modulator,Agonist, activators, activates, potent, BioCrick

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