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1604810-83-4 (THZ1)

1

Identification

THZ1 THZ1
Name THZ1
Formula C31H28ClN7O2
MW 566.05
CAS No. 1604810-83-4
EINECS
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
Synonyms CDK7 inhibitor; (E)-N-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(4-(dimethylamino)but-2-enamido)benzamide
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+
2

Introduction

THZ1 is a novel selective and potent covalent CDK7 inhibitor with IC50(binding affinity) of 3.2 nM; inhibits Jurkat cell's proliferation with IC50 of 50 nM. IC50 value: 3.2 nM (Kd for CDK7)[1] Target: CDK7 THZ1 has the unprecedented ability to target a remotecysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1.

Background Information

Novel selective covalent CDK7 inhibitor, disproportionally affecting transcription of RUNX1 ......by AOBIOUS INC
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. THZ1 causes defects in Pol II(polymerase II) phosphorylation, co-transcriptional capping, promoter proximal pausing, and productive elongation. 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. ......by AbMole BioScience
THZ1 is a novel selective and potent covalent CDK7 inhibitor with IC50(binding affinity) of 3.2 nM; inhibits Jurkat cell's proliferation with IC50 of 50 nM ......by AdooQ BioScience, LLC
Description ......by Apexbio Technology LLC
THZ1 is a selective CDK7 inhibitor that preferentially diminishes transcription in cancer cells. THZ1 has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of ach ......by BOC Sciences
THZ1 is a potent, cell-permeable, and selective covalent CDK7 inhibitor (IC₅₀ = 3.2 nM) that preferentially diminishes transcription in cancer cells. It displays unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. ......by BioVision, Inc.,
THZ1 is a potent, cell-permeable, and selective covalent CDK7 inhibitor (IC₅₀ = 3.2 nM) that preferentially diminishes transcription in cancer cells. It displays unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. ......by BioVision, Inc.,
THZ1 is a selective and potent covalent CDK7 inhibitor with IC50 of 3.2 nM. ......by MedChemexpress Co., Ltd.
THZ1 is a selective CDK7 inhibitor that preferentially diminishes transcription in cancer cells. THZ1 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. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Cyclin-dependent kinases (CDKs) are involved in temporal control of the cell cycle and transcription and play central roles in cancer development and metastasis. ......by MedKoo Biosciences, Inc.
A potent, selective, covalent CDK7 inhibitor with IC50 of 3.2 nM; also weakly inhibits CDK12 with IC50 of 250 nM; displays broad-based activity a subset of cancer cell lines with IC50s of <200 nM; causes decreased cellular proliferation and an increase in apoptotic index (MCL-1, XIAP), disproportionally affects transcription of RUNX1 in Jurkat T-ALL cells; demonstrates efficacy against primary leukemia cells and in a bioluminescent xenografted model at 10mg/kg. ......by ProbeChem
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. ......by Selleck Chemicals LLC
3

Protocol(Only for Reference)

Cell Experiment

Cell lines Jurkat and Loucy T-ALL cell lines
Conditions 72 hours IC50: 50 nM (for Jurkat cells), 0.55 nM (for Loucy T-ALL cells)
Method 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.
Source Apexbio Technology LLC

Animal Experiment

Animal Models Mice bearing KOPTK1 xenografts
Dosage Form 10 mg/kg, twice daily for 29 days
Applications 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.
Source Apexbio Technology LLC
4

Physical and Chemical Properties

Appearance:White to off-white Solid EBNumber:EB000014639

Storage condition

Store at -20°C by Apexbio Technology LLC

Solubility

Soluble in DMSO by Apexbio Technology LLC
DMSO by MedChemexpress Co., Ltd.
5

Mechanism and Indication

Signaling Pathways Cell Cycle/DNA Damage
Target CDK
Research Area Cancer
Indications
6

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
THZ1 - Not Found
THZ1 - No Development Reported
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Safety Data of THZ1

8

Spectral Information

9

Suppliers List

Company Price and Availability Country/Region
AOBIOUS INC USA
AbMole BioScience USA
AdooQ BioScience, LLC 5mg/USD176() USA
Apexbio Technology LLC USA
Ark Pharm, Inc. USA
BOC Sciences
BioVision, Inc., USA
BioVision, Inc., USA
Biochempartner Co., Ltd China
CHEMSCENE, LLC 5mg/USD96();10mg/USD168() USA
Cayman Chemical Company USA
MedChemexpress Co., Ltd. 5mg/USD96();10mg/USD168() USA
MedKoo Biosciences, Inc. USA
ProbeChem
Selleck Chemicals LLC USA
Shanghai Haoyuan Chemexpress Co., Ltd. 5mg/USD96();10mg/USD168() China
Shanghai XingMo Biotechnology Co., Ltd. 1g/USD1300(In stock) CHINA
Xcess Biosciences, Inc. 2mg/USD159() USA
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Related Products

Other Forms of 1604810-83-4

Name CAS No Formula MW

Recommended Compounds in CDK

Name CAS No Formula MW
LY2857785 1619903-54-6 C26H36N6O 448.6
THZ2 1604810-84-5 C31H28ClN7O2 566.0527
Palbociclib (isethionate) 827022-33-3 C26H35N7O6S 573.66
CDK9-IN-6 1391855-95-0 C27H37ClN6O2 513.07468
ML167 1285702-20-6 C19H17N3O3 335.36
AMG 925 1401033-86-0 C26H29N7O2 471.55
LDC000067 1073485-20-7 C18H18N4O3S 370.43
LEE011 (succinate hydrate) 1374639-79-8 C27H38N8O6X 570.64
LEE011 (succinate) 1374639-75-4 C27H36N8O5 552.63
LEE011 (hydrochloride) 1211443-80-9 C23H31ClN8O 471.0
LEE011 1211441-98-3 C23H30N8O 434.54
WHI-P180 (hydrochloride) 153437-55-9 C16H16ClN3O3 333.77
Wogonin 632-85-9 C16H12O5 284.26
1-NM-PP1 221244-14-0 C20H21N5 331.41
WHI-P180 211555-08-7 C16H15N3O3 297.31
Senexin A 1366002-50-7 C17H14N4 274.32
CDK4-IN-1 1256963-02-6 C22H29ClN8 440.97
Palbociclib (hydrochloride) 827022-32-2 C24H30ClN7O2 483.99
Purvalanol B 212844-54-7 C20H25ClN6O3 432.9
NU6102 444722-95-6 C18H22N6O3S 402.47

Recommended Compounds in Same Indication

Name CAS No Formula MW
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Route of Synthesis

12

References

[1]. Nicholas Kwiatkowski, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature (2014) doi:10.1038/nature13393

Protocol Reference

[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.

......by Apexbio Technology LLC
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More Information

THZ1

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