Background
AT7519 is a small-molecule inhibitor of cyclin-dependent kinases (CDKs) with IC50 values of 210, 47, 100, 13, 170 and <10 nM for CDK1, CDK2, CDK4, CDK5, CDK6 and CDK9, respectively [1].
AT7519 showed no inhibition activity against CDK3, 7 and other non-CDK kinases. It inhibited CDK1 in an ATP- competitive manner with Ki value of 38 nM. AT7519 potently inhibited the proliferation of various human tumor cell lines and this activity is cell cycle related. AT7519 was also effective in cell lines with p53 mutants or suppression, suggesting that the anti-proliferation efficacy is p53-independent. In HCT116 cells, 24 h-treatment of AT7519 resulted in a remarkable induction of G0-G1 and G2-M cell cycle arrest. Besides that, AT7519 at concentrations relating to IC50 induced cell apoptosis (24 h) in HCT116, A2780 and HT29 cells with 52%, 3% and 94% survival, respectively. Moreover, in HCT116 tumor-bearing mice, 10 mg/kg AT7519 with intraperitoneal injection caused inhibition of NPM phosphorylation and induced apoptosis [1, 2].
参考文献:
[1] Squires M S, Feltell R E, Wallis N G, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Molecular cancer therapeutics, 2009, 8(2): 324-332.
[2] Wyatt P G, Woodhead A J, Berdini V, et al. Identification of N-(4-Piperidinyl)-4-(2, 6-dichlorobenzoylamino)-1 H-pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design?. Journal of medicinal chemistry, 2008, 51(16): 4986-4999.
Protocol
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Cell experiment [1]:
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Cell lines
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MM(multiple myeloma) cell lines including MM.1S, MM.1R, RPMI8226 human MM cells ,U266 human MM cells, Melphalan-resistant (LR5) RPMI8266 human MM cells, doxorubicin-resistant RPMI-Dox40 MM cells
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Preparation method
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Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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0.5 μM for 6, 12 and 24 h
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Applications
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Anti-MM activity of AT7519 displayed potent cytotoxicity and apoptosis. AT7519 inhibited RNA polymerase II phosphorylation, associated with decreased RNA synthesis. Additionally, AT7519 inhibited glycogen synthase kinase 3 beta (GSK-3β) phosphorylation, suggesting the involvement of GSK-3β in AT7519-induced apoptosis.
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Animal experiment [2]:
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Animal models
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Female ICR severe combined immunodeficient mice bearing HCT116 cells xenografts
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Dosage form
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4.6 and 9.1 mg/kg/dose, twice in a 24h period, respectively at 0h, 8h, for 9 consecutive days
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Application
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Suppression of phospho-NPM(nucleophosmin) due to the treating of AT7519 could induce an apoptopic response. AT7519 inhibited tumor growth and induced tumor cell apoptosis in human tumor xenograft models.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Santo L1, Vallet S, 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. doi: 10.1038/onc.2009.510. Epub 2010 Jan 25.
[2]. Squires M S, Feltell R E, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Molecular cancer therapeutics, 2009, 8(2): 324-332.
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