A Cdk inhibitor
IC50: AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines.
Cyclin-dependent kinases (CDK) play a central role in the growth, division, and death of eukaryotic cell. This crucial role in cell cycle progression and their deregulation in several human cancers make them attractive therapeutic oncology targets. Series of CDK inhibitors was developed, among which, AT7519 is in early-phase clinical development currently.
In vitro: AT7519 showed potent antiproliferative activity (40-940 nmol/L)in a panel of human tumor cells, and the mechanism of action was shown to be consistent with the inhibition of CDK1 and CDK2. Cell cycle arrest caused by AT7519 followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models [1].
In vivo: Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. The authors show that these effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis [1].
Clinical trial: A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. 4 patients with stable disease for >6 months and one had a prolonged partial response. Pharmacokinetic profile indicated modest interpatient variation with linear exposure at increased doses. AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation [2].
参考文献:
[1] Squires MS, Feltell RE, Wallis NG, Lewis EJ, Smith DM, Cross DM, Lyons JF, Thompson NT.Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther. 2009;8(2):324-32.
[2] Mahadevan D, Plummer R, Squires MS, Rensvold D, Kurtin S, Pretzinger C, Dragovich T, Adams J, Lock V, Smith DM, Von Hoff D, Calvert H. A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. Ann Oncol. 2011;22(9):2137-43.
Cell experiment: | AT7519's effects on viability of MM cell lines, primary MM cells, and PBMNCs is assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrasodium bromide (MTT) dye absorbance. DNA synthesis is measured by tritiated thymidine uptake (3H-TdR). MM cells (2-3 × 104 cells/well) are incubated in 96-well culture plates with media and different concentrations of AT7519 and/or recombinant IL-6 (10 ng/mL) or IGF-1 (50 ng/mL) for 24 or 48 h at 37°C and 3H-TdR incorporation is measured. |
Animal experiment: | To evaluate the in vivo anti-MM activity of AT7519, male SCID mice are inoculated subcutaneously with 5×106 MM.1S cells in 100 μL serum-free RPMI 1640 medium. When tumors are measurable, mice are treated intraperitoneally (IP) with vehicle or AT7519 dissolved in saline 0.9%. The first group of 10 mice is treated with 15 mg/kg once a day for five days for 2 weeks, and the second group is treated with 15 mg/kg once a day three times a week for four consecutive weeks. The control group receives the carrier alone at the same schedule. Tumor size is measured every alternate day in 2 dimensions using calipers, and tumor volume is calculated with the formula: V= 0.5 a × b2 (a= long diameter of the tumor, b= short diameter of the tumor). Animals are sacrificed when the tumor reaches 2 cm3 or when the tumor is ulcerated. Survival and tumor growth are evaluated from the first day of treatment until death. |
参考文献: [1]. Santo L, et al. AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition. Oncogene. 2010 Apr 22;29(16):2325-36. | |
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