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 Experiment | |
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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 |
Animal Experiment | |
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Animal models | |
Formulation | Dissolved in 0.9% saline |
Dosages | 15 mg/kg/day |
Administration | Dosed i.p. |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
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.
Molecular Weight | 418.71 |
Formula | C16H18Cl3N5O2 |
CAS Number | 902135-91-5 |
Purity | >99% |
Solubility | DMSO |
Storage | at -20°C |
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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