AT7519 is a novel small molecule multi-cyclin-dependent kinase inhibitor.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 cell lines (MM.1S, U266, OPM1, RPMI, LR5, DOX 40, MM.1R) and primary CD138+ MM cells|
|Preparation method||Cell viability and proliferation assays.
AT7519's effects on viability of MM cell lines, primary MM cells, and PBMNCs was assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrasodium bromide (MTT; Chemicon International) dye absorbance as previously described (Raje et al., 2009). DNA synthesis was measured by tritiated thymidine uptake (3H-TdR; Perkin Elmer). MM cells (2–3 × 104cells/well) were incubated in 96-well culture plates (Costar, Cambridge, MA) 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 was measured as previously described (Raje et al., 2009).
|Incubation time||48 h|
|Animal models||MM xenograft mouse model|
|Formulation||dissolved in saline 0.9%|
|Dosages||15 mg/kg once a day for five days for 2 weeks|
|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.
|Source||Oncotarget (2017). Figure 6. AT7519|
|Cell Lines||CRC cells|
|Incubation Time||24 or 48 h|
|Results||The results from the above experiment are summarized in Figure 6A. 20-223 and AT7519 both effectively arrested the CRC cells in either the G2 or S phase of the cell cycle.|
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 L, et al. Oncogene. 2010 Apr 22;29(16):2325-36. PMID: 20101221.
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