product name THZ1
Description: 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. 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.
References: Nature. 2014 Jul 31;511(7511):616-20; Mol Cell. 2015 Aug 20;59(4):576-87.
566.05
Formula
C31H28ClN7O2
CAS No.
1604810-83-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 28.3mg/mL
Water: <1 mg/mL
Ethanol:
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: 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. Kinase Assay: THZ1 is a novel selective and potent covalent CDK7 inhibitor with IC50(binding affinity) of 3.2 nM. Cell Assay: Cells (Jurkat, Loucy, KOPTK1 and DND-41 cell lines) are treated with THZ1, THZ1-R or dimethylsulphoxide (DMSO) for 0-6 h to assess the effect of time on the THZ1-mediated inhibition of RNAPII CTD phosphorylation. For subsequent experiments cells are treated with compounds for 4 h as determined by the time-course experiment described earlier, unless otherwise noted. For inhibitor washout experiments, cells are treated with THZ1, THZ1-R or DMSO for 4 h. Medium containing inhibitors is subsequently removed to effectively washout the compound and the cells are allowed to grow in the absence of inhibitor. For each experiment, lysates are probed for RNAPII CTD phosphorylation and other specified proteins. |
|---|---|
| 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 |
| Animal model | Bioluminescent xenografted mouse model |
| Formulation & Dosage | Formulated in 10% DMSO in D5W; 10 mg/kg; i.v. injection |
| References | Nature. 2014 Jul 31;511(7511):616-20; Mol Cell. 2015 Aug 20;59(4):576-87. |
