1. Cell Cycle/DNA Damage
  2. CDK

THZ1 (Synonyms: CDK7 inhibitor)

Cat. No.: HY-80013 Purity: 98.82%
Handling Instructions

THZ1 is a selective and potent covalent CDK7 inhibitor with IC50 of 3.2 nM.

For research use only. We do not sell to patients.

THZ1 Chemical Structure

THZ1 Chemical Structure

CAS No. : 1604810-83-4

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Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO USD 120 In-stock
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Estimated Time of Arrival: December 31
5 mg USD 96 In-stock
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Estimated Time of Arrival: December 31
10 mg USD 168 In-stock
Stock in Sweden
Estimated Time of Arrival: December 31
50 mg USD 720 In-stock
Stock in Sweden
Estimated Time of Arrival: December 31
100 mg USD 1200 In-stock
Stock in Sweden
Estimated Time of Arrival: December 31
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Customer Review

Other Forms of THZ1:

    THZ1 purchased from MCE. Usage Cited in: Oncogenesis. 2017 May 15;6(5):e336.

    Lysates from cells treated with vehicle or 200 nM THZ1 for 48 h analyzed for the activation status of multiple CDKs as indicated to the right of panels by western blotting.

    THZ1 purchased from MCE. Usage Cited in: Oncotarget. 2017 Apr 18;8(16):27353-27363.

    Representative Western blot showing the phosphorylation status of ERα at serine 118 (S118) in MCF-7 cells in controls and after treatment with the CDK7 inhibitor, THZ1 (100 nM), or AG-490 (100 μM) for 3 h prior to E2 treatment for 30 min. Endogenous ERα and β-actin are used as loading controls.

    THZ1 purchased from MCE. Usage Cited in: Mol Cancer Ther. 2017 Sep;16(9):1739-1750.

    Western blot analysis of RNAPII CTD phosphorylation in ovarian cancer cells that are treated with THZ1.

    THZ1 purchased from MCE. Usage Cited in: Mol Cancer Ther. 2017 Sep;16(9):1739-1750.

    Western blot analysis of RNAPII CTD phosphorylation in ovarian cancer cells that are treated with THZ1.

    THZ1 purchased from MCE. Usage Cited in: Mol Cancer Ther. 2017 Sep;16(9):1739-1750.

    Western blot analysis of RNAPII CTD phosphorylation in ovarian cancer cells that are treated with THZ1.

    THZ1 purchased from MCE. Usage Cited in: TUMOR, 2017, 37(11): 1119-1127.

    The expression level of cyclin-dependent kinase 7 (CDK7) and the phosphorylation level of RNA polymeraseⅡ carboxyl-terminal domain Ser-5 (RNAPolⅡS5) in ovarian cancer cells treated with THZ1 are detected by Western blotting. After the ovarian cancer IGROV1, OVCA433, SKOV3 and COV413B cells are treated with 0.5 μM THZ1 for 0, 4, 8, 12 and 24 h, the CDK7 expression and RNAPolⅡS5 phosphorylation levels are significantly down-regulated.

    THZ1 purchased from MCE. Usage Cited in: bioRxiv. February 25, 2018.

    21mers are synthesized in parallel reactions with unlabeled (upper panel) or radiolabeled (lower panel) ribonucleoside triphosphates in the presence of DMSO (-) or increasing amounts of THZ1; reactions are stopped after 15 or 60 min.
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    THZ1 is a selective and potent covalent CDK7 inhibitor with IC50 of 3.2 nM.

    IC50 & Target[1]

    CDK7

    3.2 nM (IC50)

    In Vitro

    THZ1 inhibits Jurkat cell and Loucy cell with IC50 of 50 nM, and 0.55 nM, respectively. THZ1 demonstrates time-dependent inhibition of CDK7 in vitro and covalent binding of intracellular CDK7. THZ1 (9, 27, 83, 250, 750, and 2500 nM) inhibits CDK12 but at higher concentrations compared to CDK7. THZ1 (1 μM) irreversibly inhibits RNAPII CTD and CAK phosphorylation. THZ1 (2.5 µM) irreversibly inhibits RNAPII CTD phosphorylation by covalently targeting a unique cysteine located outside the kinase domain of CDK7 in Hela S3 cells. THZ1 (250 nM) causes decreased cellular proliferation and an increase in apoptotic index with concomitant reduction in anti-apoptotic proteins, most notably MCL-1 and XIAP in T-ALL cell lines[1]. Low-dose THZ1 (50 nM) treatment causes selective inhibition of a number of oncogenic transcripts in oesophageal squamous cell carcinoma (OSCC)[2]. All genotypically-distinct human (hSCLC) cell lines exhibit high sensitivity to THZ1, with an IC50 in the range of 5-20 nM[3].

    In Vivo

    THZ1 (10 mg/kg) demonstrates potent killing of primary chronic lymphocytic leukemia (CLL) cells and anti-proliferative activity against primary TALL cells and in vivo against a human T-ALL xenograft[1].THZ1 (10 mg/kg, i.p.) completely suppresses oesophageal squamous cell carcinoma tumour growth in vivo without loss of body weight or other common toxic effects[2]. THZ1 (10 mg/kg, i.v.) inhibits tumor growth in a mouse model of human MYCN-amplified NB and shows no toxicity[4].

    References
    Preparing Stock Solutions
    Concentration Volume Mass 1 mg 5 mg 10 mg
    1 mM 1.7666 mL 8.8331 mL 17.6663 mL
    5 mM 0.3533 mL 1.7666 mL 3.5333 mL
    10 mM 0.1767 mL 0.8833 mL 1.7666 mL
    Please refer to the solubility information to select the appropriate solvent.
    Kinase Assay
    [1]

    For kinase assays following immunoprecipitation of FLAG-CDK7 protein from HCT116 or FLAG-CDK12 from 293A cellular lysates, cells are first treated with THZ1, THZ1-R, or DMSO for 4 hrs at 37°C. Cells are then harvested by lysis in 50 mM Tris HCl pH 8.0, 150 mM NaCl, 1% NP-40, 5 mM EDTA, and protease/phosphatase cocktails. Exogenous CDK7 or CDK12 proteins are immunoprecipitated from cellular lysates using FLAG antibody- conjugated agarose beads. Precipitated proteins are washed with lysis buffer 6 times, followed by 2 washes with kinase buffer (40 mM Hepes pH 7.5, 150 mM NaCl, 10 mM MgCl2, 5% glycerol) and subjected to in vitro kinase assays at 30°C for 45 minutes using 1 μg of the large subunit of RNAPII (RPB1) as substrate and 25 μM ATP and 10 μCi of 32P ATP. Kinase assays using recombinant CDK7/TFIIH/MAT1 are conducted in the manner as described above using 25 ng of CAK complex per reaction. For kinase assays designed to test time-dependent inactivation of CDK7 kinase activity, CAK complex is pre-incubated with indicated concentrations of THZ1, THZ1-R, or DMSO in kinase buffer without ATP for 4 hrs at 30°C prior to being subjected to kinase assay conditions[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [1]

    THZ1 is dissolved in DMSO, and then diluted with appropriate media before use[1].

    Jurkat, Loucy, KOPTK1, and DND-41 cell lines are seeded in 384-well microplates at 15% confluency in medium with 5% FBS and penicillin/streptavidin. Cells are treated with THZ1 (2, 10, 50, 250, 1250, and 6250 nM) or DMSO for 72 hrs and cell viability is determined using resazurin[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    THZ1 is prepared in 10 % DMSO in 5 % glucose water[1].

    Mice[1]
    Thirty-two NOD-SCIDIL2Rcγnull (NSG) 9-week old female mice are divided into treatment groups based on mean BLI as follows: THZ1 10 mg/kg qD, THZ1 10 mg/kg BID, and vehicle (10% DMSO in D5W) BID (n=10 for all groups). Two mice are excluded, one with the highest and one with the lowest BLI. All treatments are administered via IV injection in the lateral tail vein in a volume of 3.3 μL/g (non-blinded). Mice are imaged and weighed every 3-5 days. Mice are treated for four weeks and on the final day mice are imaged, dosed and sacrificed approximately 5-6 hrs post dose. Upon sacrifice, blood is collected via cardiac puncture in EDTA tubes; a portion (300 uL) is processed for plasma. Liver and spleen tissues are collected from each mouse with half of each sample flash frozen and half of each sample fixed. Blood plasma and liver samples are processed for pharmacokinetics analysis of THZ1. Spleen tissues are homogenized and lysed and processed for pharmacodynamics analysis of THZ1 target engagement. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    566.05

    Formula

    C₃₁H₂₈ClN₇O₂

    CAS No.

    1604810-83-4

    SMILES

    ClC1=CN=C(NC2=CC(NC(C3=CC=C(NC(/C=C/CN(C)C)=O)C=C3)=O)=CC=C2)N=C1C4=CNC5=CC=CC=C54

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    DMSO: ≥ 27 mg/mL

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    Purity: 98.82%

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    Product Name:
    THZ1
    Cat. No.:
    HY-80013
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