Wnt-C59 (C59) effectively suppresses PORCN activity at nanomolar levels in vitro, evidenced by its ability to inhibit Wnt palmitoylation, the interaction of Wnt with its transporter Wntless/WLS, the secretion of Wnt, and the activation of β-catenin reporter activity by Wnt. It prevents WNT3A-induced activation of a TCF-binding site multimer driving luciferase production with an IC50 of 74 pM[1].
体内研究
In mice, Wnt-C59 shows favorable bioavailability and halts the development of mammary tumors in MMTV-WNT1 transgenic mice by reducing the expression of Wnt/β-catenin target genes[1].
Wnt-C59 holds promise for eliminating cancer stem cells within human tumors, demonstrating a capacity to diminish the stemness of NPC cells in a dose-dependent manner through the inhibition of sphere formation in both HNE1 and SUNE1 cell lines[2].
体外研究
Wnt-C59 (C59) effectively suppresses PORCN activity at nanomolar levels in vitro, evidenced by its ability to inhibit Wnt palmitoylation, the interaction of Wnt with its transporter Wntless/WLS, the secretion of Wnt, and the activation of β-catenin reporter activity by Wnt. It prevents WNT3A-induced activation of a TCF-binding site multimer driving luciferase production with an IC50 of 74 pM[1].
作用机制
Serine acylation in Wnt protein is essential in Wnt secretion. PORCN is a key enzyme that resides in the endoplasmic reticulum, adding palmitate to a serine in Wnt protein. Wnt-C59 acts as a nanomolar inhibitor of the acyltransferase activity of PORCN.
Wnt-C59 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary kidney fibroblasts
10 nM
24 h
To study the effect of Wnt-C59 on TGF-β-induced Axin2 expression, results showed that Wnt-C59 significantly inhibited Axin2 expression.
Kidney Int. 2016 May;89(5):1062-1074.
HK-2 cells
10 nM
24 h
To study the effect of Wnt-C59 on TGF-β-induced Axin2 expression, results showed that Wnt-C59 significantly inhibited Axin2 expression.
Kidney Int. 2016 May;89(5):1062-1074.
CC-SW-1
100 nM
10 days
Inhibition of PORCN activity resulted in reduced cell number, indicating Wnt-C59 has an inhibitory effect on CC-SW-1 cells in vitro
J Clin Invest. 2015 Mar 2;125(3):1269-85.
SNU-1196
100 nM
10 days
Inhibition of PORCN activity resulted in reduced cell number, indicating Wnt-C59 has an inhibitory effect on SNU-1196 cells in vitro
J Clin Invest. 2015 Mar 2;125(3):1269-85.
WITT-1
100 nM
10 days
Inhibition of PORCN activity resulted in reduced cell number, indicating Wnt-C59 has an inhibitory effect on WITT-1 cells in vitro
J Clin Invest. 2015 Mar 2;125(3):1269-85.
SNU-1079
100 nM
10 days
Inhibition of PORCN activity resulted in reduced cell number, indicating Wnt-C59 has an inhibitory effect on SNU-1079 cells in vitro
J Clin Invest. 2015 Mar 2;125(3):1269-85.
CC-LP-1
100 nM
10 days
Inhibition of PORCN activity resulted in reduced cell number, indicating Wnt-C59 has an inhibitory effect on CC-LP-1 cells in vitro
J Clin Invest. 2015 Mar 2;125(3):1269-85.
intestinal organoids
100 nM
24 h
Wnt-C59 inhibited the protective effect of L. reuteri on intestinal organoids, leading to increased damage induced by C. rodentium, reduced expression of Wnt3, Lgr5, and R-spondin1, and inhibition of Paneth cell differentiation and antimicrobial peptide expression, accompanied by increased inflammatory cytokine expression.
Gut Microbes. 2020 Jul 3;11(4):997-1014.
8591-GSCs
20 μM
24 h
inhibited invasion and migration
J Exp Clin Cancer Res. 2018 Sep 12;37(1):225.
8591-GSCs
5 μM
24 h
inhibited invasion and migration
J Exp Clin Cancer Res. 2018 Sep 12;37(1):225.
U251-GSCs
20 μM
24 h
inhibited invasion and migration
J Exp Clin Cancer Res. 2018 Sep 12;37(1):225.
U251-GSCs
5 μM
24 h
inhibited invasion and migration
J Exp Clin Cancer Res. 2018 Sep 12;37(1):225.
PM cells
5 μM
72 h
WNT-C59 significantly reduced the growth stimulating effect of Meso-CAFs on PM cells in co-culture, but did not significantly affect PM cells alone.
J Exp Clin Cancer Res. 2023 Jan 23;42(1):27.
imMKCLs
1.1 µM
7 days
Promote MK maturation and PLP production
Blood Adv. 2018 Sep 11;2(17):2262-2272.
Wnt-C59 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Unilateral ureteral obstruction model
Oral gavage
25 mg/kg
Once daily for 7 days
To study the effect of Wnt-C59 on renal fibrosis in the unilateral ureteral obstruction model, results showed that Wnt-C59 significantly attenuated kidney fibrosis and reduced collagen mRNA expression.
Kidney Int. 2016 May;89(5):1062-1074.
Mice
C57BL/6J mice
Oral
100 mg/kg
Single dose, sacrificed 24 hours later
To examine the early effects of withdrawal of Wnt signaling in ISC proliferation, results showed a significant increase in proliferating cells in crypt base cells in the duodenum, jejunum, and ileum in C59-treated mice
J Clin Invest. 2018 Aug 31;128(9):3806-3812
Rats
Chemically induced cholangiocarcinoma model
Intraperitoneal injection
20 mg/kg
3 times per week for 5 weeks
Inhibition of the Wnt signaling pathway significantly reduced tumor size and number, indicating Wnt-C59 has therapeutic potential for cholangiocarcinoma in vivo
J Clin Invest. 2015 Mar 2;125(3):1269-85.
Mice
C. rodentium infection model
Oral
5 mg/kg
Once daily for 16 days
Wnt-C59 reversed the protective effect of L. reuteri against C. rodentium infection, leading to increased weight loss, C. rodentium colonization, and pathological changes, reduced expression of Wnt3, Lgr5, and R-spondin1, and inhibition of Paneth cell differentiation and antimicrobial peptide expression, accompanied by increased inflammatory cytokine and LPS levels.
Gut Microbes. 2020 Jul 3;11(4):997-1014.
BALB/c-nu mice
Intracranial orthotopic xenograft model
Oral administration
15 mg/kg
Daily until the end of the experiment
Inhibited tumor growth and prolonged survival time
J Exp Clin Cancer Res. 2018 Sep 12;37(1):225.
C57BL/6JRj mice
Anti-GPIbα antibody-induced thrombocytopenia model
Intraperitoneal injection
100 mg/kg
Once daily for 6 days
Evaluate the effect of Wnt-C59 on promoting platelet recovery in vivo
Blood Adv. 2018 Sep 11;2(17):2262-2272.
Mice
Bile duct ligation model
Intraperitoneal injection
30 mg/kg
Once daily for 5 or 12 days
Wnt-C59 significantly reduced the number of bile infarcts and inflammatory cells in the liver in the BDL model, suppressed the nuclear factor kappa B signaling pathway, and reduced cholestatic injury.
Wnt-C59 was used to inhibit the Wnt signaling pathway to confirm that hucMSC-exo promotes mucosal healing by activating the Wnt/β-catenin pathway. The results showed that Wnt-C59 reversed the protective effects of hucMSC-exo in colitis mice, indicating that the efficacy of hucMSC-exo depends on the activation of the Wnt/β-catenin pathway.
Inhibition of porcupine activity (unknown origin) expressed in human HT1080 cells assessed as suppression of Wnt3A-mediated super top flash activity by STF luciferase assay, IC50=7.4e-05 μM.
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