Background
Wnt-C59 is a selective inhibitor of Wnt signaling with IC50 value of 74 pM [1].
Wnt signaling pathways are a group of signal transduction pathways made of proteins and play an important role in passing signals from outside of a cell through cell surface receptors to the inside of the cell [1, 2].
Wnt-C59 is a potent Wnt inhibitor and has a different selectivity with the reported Wnt inhibitor crizotinib. When tested with HT1080 and Hela cells, Wnt-C59 showed inhibition on activation of a multimerized TCF-binding site driving luciferase mediated by Wnt3A by completely abrogating Wnt secretion [1]. In 5 human CC cell lines CC-LP-1, SUN-1079, WITT-1, SNU-1196, and CC-SW-1, Wnt-C59 treatment decreased cell viability, reduced cell proliferation and increased cell apoptosis by inhibiting Wnt signaling [2].
In C57/BL6 mice model transplanted with fragments from 2 independent primary MMTV-WNT1 tumors, oral administration of Wnt-C59 (10 mg/kg/d) for 17 days significantly arrested tumor growth and decreased tumor weights after sacrificing mice [1]. When tested with CD1 nude mice model with CC cell lines (CC-LP-1 and CC-SW-1) subcutaneous xenograft into the flanks, administration ofWnt-C59 inhibited cell growth and increased cell apoptosis compared with control group [2].
参考文献:
[1].? Proffitt, K.D., et al., Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res, 2013. 73(2): p. 502-7.
[2].? Boulter, L., et al., WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest, 2015. 125(3): p. 1269-85.
Protocol
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Cell experiment [1]:
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Cell lines
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Human CC cell lines, CC-LP-1, SNU-1079, WITT-1, SNU-1196, and CC-SW-1
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Preparation method
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The solubility of this compound in DMSO is > 19 mg/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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100 nM, 10 d
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Applications
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Inhibition of PORCN with Wnt-C59 leaded to a reduction in cell count in a dose-dependent manner in all 5 cell lines. Treating CC cells with Wnt-C59 resulted in reduction of BrdU uptake and increase of caspase-3/7 activity, indicating reduced proliferation and increased apoptosis of CC cells.
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Animal experiment [2]:
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Animal models
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Female MMTV-WNT1 mice with mammary tumors
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Dosage form
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Oral administration, 5 mg/kg
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Application
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Wnt-C59 inhibited the progression of mammary tumors in MMTV-WNT1 transgenic mice and reduced Wnt/β-catenin expression. Furthermore, Wnt-C59 exhibited good bioavailability and no apparent toxicity to mice.
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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]. Boulter L, Guest R V, Kendall T J, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited[J]. The Journal of clinical investigation, 2015, 125(3): 1269-1285.
[2]. Proffitt K D, Madan B, Ke Z, et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer[J]. Cancer research, 2013, 73(2): 502-507.
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