1. Cell Cycle/DNA Damage
  2. CDK

THZ1 Hydrochloride (Synonyms: CDK7 inhibitor)

Cat. No.: HY-80013A Purity: 98.70%
Data Sheet SDS Handling Instructions

THZ1 Hydrochloride 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 Hydrochloride Chemical Structure

THZ1 Hydrochloride Chemical Structure

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Free Sample (0.5-1 mg)   Apply now  
10 mM * 1 mL in DMSO $106 In-stock
5 mg $80 In-stock
10 mg $140 In-stock
50 mg $600 In-stock
100 mg $1000 In-stock
200 mg   Get quote  
500 mg   Get quote  

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Customer Review

Other Forms of THZ1 Hydrochloride:

    THZ1 Hydrochloride 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.

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    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

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

    IC50 & Target

    IC50: 3.2 nM (CDK7)[1]

    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 1.6597 mL 8.2986 mL 16.5972 mL
    5 mM 0.3319 mL 1.6597 mL 3.3194 mL
    10 mM 0.1660 mL 0.8299 mL 1.6597 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. Note: no additional inhibitors are added to the kinase reaction mixture, therefore any inhibition results from the activity of the compounds that are added directly to cells (ie-intracellular inhibition). This suggests that the inhibitors are either covalently tethered to the kinase or have strong non-covalent character. 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

    602.51

    Formula

    C₃₁H₂₉Cl₂N₇O₂

    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: 22.5 mg/mL

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

    Purity: 98.70%

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