Background
UNC2025 is a potent and orally bioavailable Mer/Flt3 dual inhibitor with the IC50 value of 0.8/0.74 nM for Mer/Flt3[1].
In vitro: In duplicate versus 305 kinases at Carna Biosciences using a microcapillary electrophoresis assay, UNC2025 inhibited Mer and Flt3 with the greatest potency. In B-ALL 697 cell lysates using the ATP ActivX probe assay, UNC2025 inhhibited the activity of Mer with an IC50 of 0.05 nM. In 697 B-ALL cells, UNC2025 potently inhibited Mer phosphorylation with an IC50 of 2.7 nM. Similarly, in Flt3-ITD positive Molm-14 acute myeloid leukemia cells, treatment with UNC2025 decreased phosphorylation of Flt3 with an IC50 of 14 nM. In soft agar cultures of the A549 NSCLC and Molm-14 AML cell lines, incubation withUNC2025 significantly inhibited colony formation, which was known to depend on Merand Flt3,respectively, for optimal expression of oncogenic phenotypes. Much higher concentrations of UNC2025 were required to effectively inhibit phosphorylation of Axl (IC50 = 122 nM) and Tyro3 (IC50 = 301 nM)[1].
In vivo: In mice with human leukemia xenografts, a single dose of UNC2025 (3 mg/kg) administered orally was sufficient to decrease Merphospho-protein levels in bone marrow leukemia cells by greater than 90% [1].
Reference:
[1].?Zhang W1,DeRyckere D,Hunter D,Liu J,Stashko MA,Minson KA, et,al. UNC2025, a potent and orally bioavailableMER/FLT3dual inhibitor.J Med Chem.2014 Aug 28;57(16):7031-41. doi: 10.1021/jm500749d. Epub 2014 Aug 6.
Protocol
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Cell experiment [1]:
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Cell lines
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697 B-ALL cells; Flt3-ITD positive Molm-14 acute myeloid leukemia cells; A549 NSCLC cells
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Preparation method
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The solubility of this compound in DMSO is >23.9mg/mL. 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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0-300 nM; 1 h
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Applications
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In 697 B-ALL cells, UNC2025 inhibited Mer phosphorylation with IC50 value of 2.7 nM. In Flt3-ITD positive Molm-14 acute myeloid leukemia cells, UNC2025 inhibited phosphorylation of Flt3 with an IC50 of 14 nM. In A549 NSCLC cells and Molm-14 AML cells, UNC2025 inhibited colony formation in Mer-dependent and Flt3-dependent way.
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Animal experiment [1]:
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Animal models
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mice with human leukemia xenografts
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Dosage form
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3 mg/kg; orally
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Application
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In mice with human leukemia xenografts, UNC2025 inhibited Mer phosphor-protein levels in bone marrow leukemia cells by greater than 90%.
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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]. Zhang W1,DeRyckere D,Hunter D,Liu J,Stashko MA,Minson KA, et,al. UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor. J Med Chem.2014 Aug 28;57(16):7031-41. doi: 10.1021/jm500749d. Epub 2014 Aug 6.
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