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Purity: ≥98%
THZ1 (THZ-1) is a novel, potent, selective and covalent/irreversible CDK7 inhibitor (IC50 = 3.2 nM) with anticancer activity. It has exceptional ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. 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.
| ln Vitro |
Jurkat cells and Loucy cells are inhibited by THZ1, with IC50 values of 50 nM and 0.55 nM, respectively. CDK12 is inhibited by THZ1 (9, 27, 83, 250, 750, and 2500 nM), although at higher concentrations than CDK7. THZ1 (1 μM) phosphorylates CAK and RNAPII CTD irreversibly. In Hela S3 cells, THZ1 (2.5 μM) covalently targets a specific cysteine outside the CDK7 kinase domain to irreversibly prevent RNAPII CTD phosphorylation. In T-ALL cell lines, THZ1 (250 nM) causes a drop in anti-apoptotic proteins, most notably MCL-1 and XIAP, as well as an increase in the apoptotic index and lower cell proliferation [1]. With an IC50 ranging from 5 to 20 nM, all genotyped human (hSCLC) cell lines exhibit great sensitivity to THZ1 [3].
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| ln Vivo |
THZ1 (10 mg/kg) exhibits potent killing of primary chronic lymphocytic leukemia (CLL) cells and antiproliferative activity on primary TALL cells and on human T-ALL xenografts in vivo [1]. THZ1 (10 mg/kg, iv) reduced tumor growth and demonstrated no toxicity in a human MYCN-amplified NB mouse model [4]. THZ1 (10 mg/kg, ip) fully suppresses esophageal squamous cell carcinoma tumor growth in animals without weight loss or other common adverse symptoms [5].
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| Additional Infomation |
THZ1 is a member of the class of indoles that is 1H-indole substituted by a 5-chloro-2-[3-(4-{[(2E)-4-(dimethylamino)but-2-enoyl]amino}benzamido)anilino]pyrimidin-4-yl group at position 3. It is a selective and potent covalent inhibitor of CDK7 that exhibits anti-proliferative effects in cancer cell lines. It has a role as an EC 2.7.11.22 (cyclin-dependent kinase) inhibitor and an antineoplastic agent. It is a member of indoles, an aminopyrimidine, a member of benzamides, an organochlorine compound, an enamide and a secondary carboxamide.
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| Molecular Formula |
C31H28CLN7O2
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| Molecular Weight |
566.05
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| Exact Mass |
565.199
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| CAS # |
1604810-83-4
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| Related CAS # |
bio-THZ1;1604811-14-4;THZ1-R;1621523-07-6;THZ1 Hydrochloride
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| PubChem CID |
73602827
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.735
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| LogP |
5.08
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
41
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| Complexity |
896
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN(C)C/C=C/C(=O)NC1=CC=C(C=C1)C(=O)NC2=CC=CC(=C2)NC3=NC=C(C(=N3)C4=CNC5=CC=CC=C54)Cl
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| InChi Key |
OBJNFLYHUXWUPF-IZZDOVSWSA-N
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| InChi Code |
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+
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| 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
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (8.83 mM) in 10% DMSO + 90% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2.08 mg/mL (3.67 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 .THZ1 demonstrates time-dependent inhibition of CDK7in vitroand covalent binding of intracellular CDK7.Nature.2014 Jul 31;511(7511):616-20. |
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THZ1 covalently binds CDK7 C312.Nature.2014 Jul 31;511(7511):616-20. |
THZ1 inhibits CDK12 but at higher concentrations compared to CDK7.Nature.2014 Jul 31;511(7511):616-20. |
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