Wnt-C59 (also called Wnt-C 59; C59; Wnt-C-59; C-59) is a novel, highly potent and orally bioactive PORCN (porcupine) inhibitor with potential antineoplastic activity. It inhibits Wnt3A-mediated activation of a multimerized TCF-binding site driving luciferase with an IC50 of 74 pM in HEK293 cells. Wnt-C59 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. Wnt-C59 displays good bioavailability in mice. Wnt-C59 blocks progression of mammary tumors in MMTV-WNT1 transgenic mice while downregulating Wnt/β-catenin target genes. Wnt-C59 has the potential to eradicate cancer stem cells in human tumors. Wnt-C59 inhibits stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells.
理化性质和储存条件
| Molecular Weight (MW) | 379.45 |
|---|
| Formula | C25H21N3O |
|---|
| CAS No. | 1243243-89-1 |
|---|
| Storage | -20℃ for 3 years in powder form |
|---|
| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 76 mg/mL (200.3 mM) |
|---|
| Water: <1 mg/mL |
| Ethanol: <1 mg/mL |
| Solubility (In vivo) | 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5 mg/mL |
|---|
| Synonyms | WntC59; C-59; Wnt-C 59; C59; Wnt-C59; C 59; 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide |
|---|
实验参考方法
| In Vitro | In vitro activity: Wnt-C59 (C59) is claimed to inhibit PORCN enzyme activity at nanomolar concentrations. Wnt-C59 (10 nM) blocks the palmitoylation-dependent Wnt–WLS interaction in HeLa cells transfected with either WNT3A-V5 or WNT8A-V5 plasmids. Wnt-C59 (100 nM) prevents incorporation of palmitate into WNT3A in HeLa cells transfected with WNT3A-V5, consistent with inhibition of PORCN activity. Wnt-C59 (100 nM) inhibits the activity of all splice variants of murine PORCN in PORCN-null HT1080 cells transfected with PORCN. Wnt-C59 is a nanomolar inhibitor of mammalian PORCN acyltransferase activity and blocks activation of all evaluated human Wnts. Wnt-C59 does not significantly inhibit the proliferation of any of 46 tested cancer cell lines in vitro at concentrations that completely inhibit PORCN. Wnt-C59 is capable to significantly inhibit proliferation and comparable to the ICG-001 treated NMuMG (NMG) cells. Wnt-C59 inhibits sphere formation by threefold in NMuMG (NMG) cells, which is dependent on Wnt10b-secretion. Wnt-C59 inhibits proliferation of human MDA-MB 231 cells by>50%. Wnt-C59 (a Porcupine inhibitor) blocks radiolabel incorporation of [125I]iodo-pentadecanoate in mouse L-Wnt3a cells transfected with Flag-Porcupine.
Kinase Assay: Wnt-C59 (C59) is a highly potent and oral porcupine (PORCN) inhibitor with an IC50 of 74 pM.
Cell Assay: Wnt-C59 has the potential to eradicate cancer stem cells in human tumors. Wnt-C59 inhibits stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells. |
|---|
| In Vivo | Wnt-C59 concentration remains greater than 10-fold above the in vitro IC50 for at least 16 hours following a single oral dose (5 mg/kg) in mice. Wnt-C59 (10 mg/kg) prevents growth of MMTV-WNT1 tumors in female nude mice orthotopically transplanted with independent MMTV-WNT1 tumors. Wnt-C59 (10 mg/kg) decreases Wnt pathway activity and decreased proliferation in MMTV-WNT1 tumors in female nude mice orthotopically transplanted with independent MMTV-WNT1 tumors as evident by decreased expression of β-catenin target gene expression. Wnt-C59 (10%) topically administered 4 weeks decreases the size of dysplasia of SmoM2-expressing cells in adult K14CREER/Rosa–SmoM2 mice. |
|---|
| Animal model | Female nude mice orthotopically transplanted with independent MMTV-WNT1 tumors |
|---|
| Formulation & Dosage | Dissolved in 0.5% methylcellulose and 0.1% Tween-80; 10 mg/kg; Oral gavage |
|---|
| References | Cancer Res. 2013 Jan 15;73(2):502-7; Nat Cell Biol. 2012 Dec;14(12):1282-94. |
|---|
