Background
AMG 925 is a dual inhibitor of FLT3/CDK4 kinase with IC50 values of 2nM and 3nM, respectively [1].
AMG 925 is a potent, selective, and orally available FLT3/CDK4 dual inhibitor. It also inhibits CDK6 potently in kinase assay. In acute myeloid leukemia (AML) cell lines MOLM13 and Mv4-11, AMG 925 inhibits cell growth (IC50 values of 19nM and 18nM, respectively) through inhibiting P-FLT3 and P-STAT5 and inducing apoptosis. FLT3 mutants cause resistance to the current FLT3 inhibitors. AMG 925 is reported to inhibit cell growth in AML cells with FLT3 mutants FLT3-D835Y and FLT3-D835V. In AML tumor –bearing mice, administration of AMG 925 shows inhibition of P-STAT5 and P-RB as well as cell growth both in subcutaneous MOLM13 xenograft tumor model and systemic MOLM13-Luc xenograft tumor model. AMG 925 is also reported to have antitumor activity in a dose-dependent manner in theRB-positive Colo205 colon adenocarcinoma xenograft model [1].
参考文献:
[1] Keegan K, Li C, Li Z, Ma J, Ragains M, Coberly S, Hollenback D, Eksterowicz J, Liang L, Weidner M, Huard J, Wang X, Alba G, Orf J, Lo MC, Zhao S, Ngo R, Chen A, Liu L, Carlson T, Quéva C, McGee LR, Medina J, Kamb A, Wickramasinghe D, Dai K. Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia. Mol Cancer Ther. 2014 Apr;13(4):880-9.
Protocol
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Cell experiment[1]:
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Cell lines
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MOLM13, MOLM13SR, and U937 cells
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Preparation method
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The solubility of this compound in DMSO is 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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48 h, 1 μM
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Applications
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AMG 925 is an effective and orally bioavailable dual inhibitor of FLT3 and CDK4. AMG 925 inhibits the proliferation of a batch of human tumor cell lines, including Colo205 (Rb+) and U937 (FLT3WT) cells. AMG 925 also induced apoptosis in FLT3 mutant AML cells, including MOLM13 (FLT3ITD) and MOLM13 (FLT3ITD, D835Y) cells.
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Animal experiment [2]:
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Animal models
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NCR nude mice
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Dosage form
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Oral administration with 12.5, 25, 37.5, and 50 mg/kg. Twice a day for 10 consecutive days.
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Application
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AMG 925 inhibited the growth of AML xenograft tumor in a dose-dependent manner without significant body weight loss. The concentrations of AMG 925 in plasma correlated with the inhibition of RB and STAT5 phosphorylation, which are markers for inhibition of CDK4 and FLT3, respectively.
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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]. Li Z, Wang X, Eksterowicz J, et al. Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3[J]. Journal of medicinal chemistry, 2014, 57(8): 3430-3449..
[2]. Keegan K, Li C, Li Z, et al. Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia[J]. Molecular cancer therapeutics, 2014, 13(4): 880-889.
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