AT7519 hydrochloride is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50 of 10-210 nM. AT7519 displays potent cytotoxicity and apoptosis; associated with in vivo tumor growth inhibition and prolonged survival. At the molecular level, AT7519 inhibited RNA polymerase II (RNA pol II) phosphorylation, a CDK9, 7 substrate, associated with decreased RNA synthesis confirmed by [(3)H] Uridine incorporation. In addition, AT7519 inhibited glycogen synthase kinase 3beta (GSK-3beta) phosphorylation.
|Cell lines||MM.1S, MM.1R, RPMI8226, U266, RPMI8266, RPMI-Dox40, OPM1 cells, primary MM cells and PBMNCs|
|Preparation method||Incubating cells with different concentrations of AT7519 for 24 or 48 hours at 37°C. Assaying cell viability by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrasodium bromide (MTT) dye absorbance. Measuring DNA synthesis by tritiated thymidine uptake (3H-TdR).Assessing Apoptosis by using Annexin V/PI staining. Defining the percentage of cells undergoing apoptosis as the sum of early apoptosis (Annexin V-positive cells) and late apoptosis (Annexin V-positive and PI-positive cells|
|Concentrations||Dissolved in DMSO at a concentration of 10 mM, final concentrations 0.25-4 μM|
|Incubation time||24 or 48 hoursMale SCID mice inoculated subcutaneously with MM.1S cells|
|Formulation||Dissolved in 0.9% saline|
|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.
Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation.
Alessandri, et al. PLoS One. 2011;6(9):e25683. PMID: 21984938.
A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors.
Mahadevan, et al. Ann Oncol. 2011 Sep;22(9):2137-43. PMID: 21325451.
AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples.
Squires, et al. Mol Cancer Ther. 2010 Apr;9(4):920-8. PMID: 20354122.
AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition.
Santo, et al. Oncogene. 2010 Apr 22;29(16):2325-36. PMID: 20101221.
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Voruciclib (P1446A-05) is a protein kinase inhibitor specific for the cyclin-dependent kinase 4 (CDK4) with IC50s of 90nM, 25nM, and 22nM for CDK4-CyclinD1, CDK1-Cyclin B, and CDK9-Cyclin T, respectively.
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ON123300 is a potent inhibitor of CDK4, with an IC50 of 3.8 nM, with little inhibitory activity against CDKs 1,2,5 and 8.
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