Background
VX-11e is a potent, selective, and orally bioavailable inhibitor of ERK with Ki < 2 nM.
VX-11e?is active in the HT29 cell proliferation assay (IC50=48 nM)[1].
VX-11e is orally bioavailable in both rat and mice[1]. VX-11e (50 mg/kg, p.o.) results in robust inhibition of pRSK, and inhibits tumor growth in NSG mice bearing human melanoma RPDX tumors. VX-11e with BKM120 significantly improves tumor growth inhibition[2].
参考文献:
[1]. Aronov, Alex M., et al. Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control. Journal of Medicinal Chemistry (2009), 52(20), 6362-6368.
[2]. Krepler C, et al. Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res. 2016 Apr 1;22(7):1592-602.
Protocol
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Kinase experiment [1]:
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ERK inhibition assay
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Compounds were assayed for the inhibition of ERK2 by a spectophotometric coupled-enzyme assay. In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated with various concentrations of the compounds in DMSO (2.5%) for 10 mins at 30 ℃ in 0.1 M HEPES buffer, pH = 7.5, containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvate kinase, 50 μg/mL lactate dehydrogenase and 200 μM erktide peptide. The reaction was initiated by the addition of 65 μM ATP. The rate of decrease of absorbance at 340 nM was monitored. The IC50 was evaluated from the data as a function of inhibitor concentration.
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Cell experiment [1]:
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Cell lines
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HT29 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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Reaction Conditions
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≤ 10 μM; 48 hrs
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Applications
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In HT29 cells, VX-11e potently inhibited cell proliferation with an IC50 value of 48 nM.
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Animal experiment [2]:
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Animal models
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NSG mice bearing human melanoma RPDX tumors
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Dosage form
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50 mg/kg; p.o.; b.i.d.
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Applications
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In NSG mice bearing human melanoma RPDX tumors, VX-11e (50 mg/kg, p.o.) potently inhibited pRSK and tumor growth. VX-11e, combined with BKM120, resulted in significantly improved tumor growth inhibition.
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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]. Aronov, Alex M, Tang Q, et al. Martinez-Botella, Gabriel et al. Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control. Journal of Medicinal Chemistry, 2009, 52(20): 6362-6368.
[2]. Krepler C, Xiao M, Sproesser K, et al. Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res. 2016 Apr 1;22(7):1592-602.
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