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.
|Cell lines||Jurkat, Loucy, KOPTK1 and DND-41 cell lines|
|Preparation method||Cells 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.|
|Incubation time||4 h|
|Animal models||Bioluminescent xenografted mouse model|
|Formulation||10% DMSO in D5W|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||100 mg/mL in DMSO|
THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing.
Nilson KA, et al. Mol Cell. 2015 Aug 20;59(4):576-87. PMID: 26257281.
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.
Kwiatkowski N, et al. Nature. 2014 Jul 31;511(7511):616-20. PMID: 25043025.
|Related CDK Products|
Palbociclib is a highly specific inhibitor of Cdk4 (IC50=11 nM) and Cdk6 (IC50=16 nM), having no activity against a panel of 36 additional protein kinases.
M2I-1 a small Mad2 inhibitor-1. the first small molecule inhibitor targeting the binding of Mad2 to Cdc20, an essential proteinprotein interaction (PPI) within the SAC.
NU2058 is a guanine-based CDK inhibitor with IC50 of 17 μM and 26 μM for CDK2 and CDK1.
LDC000067 is a highly selective CDK9 inhibitor with IC50 of 44 nM, 55/125/210/ >227/ >227-fold selectivity over CDK2/1/4/6/7.
RO-3306 is an ATP-competitive, and selective CDK1 inhibitor with Ki of 20 nM, >15-fold selectivity against a diverse panel of human kinases.
Products are for research use only. Not for human use. We do not sell to patients.
© Copyright 2010-2017 AbMole BioScience. All Rights Reserved.