Wnt-C59 | CAS#1243243-89-1 | Porcupine Inhibitor

MedKoo Cat#: 406605 | Name: Wnt-C59

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Wnt-C59 is a potent porcupine (PORCN) inhibitor. Wnt-C59 inhibits PORCN activity in vitro at nanomolar concentrations, as assessed by inhibition of Wnt palmitoylation, Wnt interaction with the carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of β-catenin reporter activity. In mice, Wnt-C59 displayed good bioavailability, as once daily oral administration was sufficient to maintain blood concentrations well above the IC(50). C59 blocked progression of mammary tumors in MMTV-WNT1 transgenic mice while downregulating Wnt/β-catenin target genes. Porcupine (PORCN) is a membrane bound O-acyltransferase that is required for Wnt palmitoylation, secretion, and biologic activity.

Chemical Structure

Wnt-C59

CAS#1243243-89-1

Theoretical Analysis

MedKoo Cat#: 406605

Name: Wnt-C59

CAS#: 1243243-89-1

Chemical Formula: C25H21N3O

Exact Mass: 379.1685

Molecular Weight: 379.45

Elemental Analysis: C, 79.13; H, 5.58; N, 11.07; O, 4.22

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,750.00	Ready to ship
1g	USD 4,250.00	Ready to ship
2g	USD 6,750.00	2 Weeks

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Synonym

WntC59; Wnt-C 59; Wnt-C59

IUPAC/Chemical Name

2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide

InChi Key

KHZOJCQBHJUJFY-UHFFFAOYSA-N

InChi Code

InChI=1S/C25H21N3O/c1-18-15-22(12-14-27-18)20-6-4-19(5-7-20)16-25(29)28-24-10-8-21(9-11-24)23-3-2-13-26-17-23/h2-15,17H,16H2,1H3,(H,28,29)

SMILES Code

O=C(NC1=CC=C(C2=CC=CN=C2)C=C1)CC3=CC=C(C4=CC(C)=NC=C4)C=C3

Appearance

White to off-white solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#CRB50618

QC Data

View QC data: current batch, Lot#CRB50618

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Wnt-C59 (C59) is a PORCN inhibitor for Wnt3A-mediated activation of a multimerized TCF-binding site driving luciferase with IC50 of 74 pM in HEK293 cells.

In vitro activity:

It was found that Wnt-C59 (C59) indeed functions as a bona fide PORCN inhibitor using a number of cell-based assays. C59 inhibits WNT3A-mediated activation of a multimerized TCF-binding site driving luciferase (Super8xTopFlash; STF) with an IC50 of 74 pmol/L (Fig. 1A). As expected for a PORCN inhibitor, Wnt secretion into culture medium is completely abrogated by C59 treatment (Fig. 1A, inset). Consistent with C59 targeting PORCN, overexpression of PORCN rescues the inhibition of WNT3A-mediated STF activity, similar to that of an unrelated PORCN inhibitor IWP-1 (refs. 21, 22; Fig. 1B). Wnt acylation is required for binding to the carrier protein WLS. WNT3A and WNT8A coimmunoprecipitate with WLS, but this interaction is blocked when cells have been pretreated with C59 (Fig. 1C). Using alkyne palmitic acid and click chemistry, it was found that C59 prevents incorporation of palmitate into WNT3A, consistent with inhibition of PORCN activity (Fig. 1D). C59 inhibits the activity of all splice variants of murine PORCN (Fig. 2A). In preliminary studies, we found that very high concentrations of C59 were required to produce developmental phenotypes in Xenopus embryogenesis. Consistent with this, while Xenopus laevis PORCN was active when expressed in PORCN-null human cells, its activity was resistant to inhibition by C59 (Fig. 2A). Because the Xenopus protein is 77% identical to human PORCN, this provides genetic evidence that PORCN is the molecular target of C59, suggests a mechanism for C59 drug resistance to emerge, and indicates that less related MBOAT proteins would also be unaffected by C59. Showing that inhibition of PORCN is likely to prevent all Wnt-mediated signaling, it was found that 9 of 9 β-catenin activating Wnts and 4 of 4 additional noncanonical Wnts lost activity when cells were treated with C59 (Fig. 2B and C). In summary, C59 is a nanomolar inhibitor of mammalian PORCN acyltransferase activity and blocks activation of all evaluated human Wnts. Thus, it’s possible that C59 administration will prevent all human and murine Wnt-dependent signaling. Reference: Cancer Res. 2013 Jan 15;73(2):502-7. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23188502

In vivo activity:

Both SUNE1 and HNE1 cell lines were chosen due to their distinct growth dynamics for animal studies. The hypothesis is if Wnt signaling was dominant in the control of cellular stemness and proliferation, it would be possible to demonstrate the inhibitory effects by Wnt-C59 in these cell lines. Wnt-C59 treatment obviously delayed the growth of SUNE1 cells immediately after administration of tested chemicals in animals, but expression of active β-catenin protein was detected in tumor stroma. The findings suggested that Wnt-C59 was not able to fully control the CSC microenvironment to favor SUNE1-induced tumor growth in animals. It was also possible that some unknown negative feedback or redundant regulatory mechanisms finally dominated the signaling networks that caused restoration of Wnt activities and tumor cell proliferation in SUNE1 cells. To detect long-term effects of Wnt-C59 in animals, which have not been reported yet, the tumor growth of HNE1 cells was investigated. These cells require a longer latency period to form growing tumors in mice, reflecting greater intra-tumoral heterogeneity in this cell line. In the control group, surviving tumor cells, presumably CSCs, expanded in the injection sites and formed progressively growing tumors very quickly after the latency period. In contrast, injected tumor cells died and did not form visible and progressively growing tumors after the treatment of Wnt-C59 in animals. It was not possible to directly show the presence of CSCs in injected HNE1 cells, but the sphere inhibition assay demonstrates that Wnt-C59 could safely eliminate cells with stemness properties in an irreversible manner. Reference: Oncotarget. 2015 Jun 10;6(16):14428-39. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25980501

	Solvent	mg/mL	mM
Solubility
	DMSO	50.0	131.77

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 379.45 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

1. Cheng Y, Phoon YP, Jin X, Chong SY, Ip JC, Wong BW, Lung ML. Wnt-C59 arrests stemness and suppresses growth of nasopharyngeal carcinoma in mice by inhibiting the Wnt pathway in the tumor microenvironment. Oncotarget. 2015 Jun 10;6(16):14428-39. doi: 10.18632/oncotarget.3982. PMID: 25980501; PMCID: PMC4546477. 2. Proffitt KD, Madan B, Ke Z, Pendharkar V, Ding L, Lee MA, Hannoush RN, Virshup DM. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 2013 Jan 15;73(2):502-7. doi: 10.1158/0008-5472.CAN-12-2258. Epub 2012 Nov 27. PMID: 23188502.

In vivo protocol:

1: Paul MA, Wainwright CL, Hector EE, Ryberg E, Leslie SJ, Walsh SK. Short-Term Oral Administration of the Porcupine Inhibitor, Wnt-c59, Improves the Structural and Functional Features of Experimental HFpEF. Pharmacol Res Perspect. 2025 Feb;13(1):e70054. doi: 10.1002/prp2.70054. PMID: 39743495; PMCID: PMC11693437. 2: Guo T, Zhang S, Zeng W, Liang Y, Xie J, Liu S, Qiu Y, Fu Y, Ou Y, Ma K, Wang B, Gu W, Duan Y. Isolation and identification of patient-derived liver cancer stem cells and development of personalized treatment strategies. J Transl Med. 2024 Nov 18;22(1):1036. doi: 10.1186/s12967-024-05870-9. PMID: 39558364; PMCID: PMC11575129. 3: Wang X, Zhang Z, Shi Y, Zhang W, Su C, Wang D. Construction of a Novel Mitochondria-Associated Gene Model for Assessing ESCC Immune Microenvironment and Predicting Survival. J Microbiol Biotechnol. 2024 May 28;34(5):1164-1177. doi: 10.4014/jmb.2310.10052. Epub 2024 Feb 22. PMID: 38719775; PMCID: PMC11180922. 4: Wang Y, Ji L, Ji C, Wang F. Multi-omics approaches establishing histone modification based prognostic model in glioma patients and further verification of the carcinogenesis mechanism. Funct Integr Genomics. 2023 Sep 21;23(4):307. doi: 10.1007/s10142-023-01229-3. PMID: 37730879. 5: Ayers M, Kosar K, Xue Y, Goel C, Carson M, Lee E, Liu S, Brooks E, Cornuet P, Oertel M, Bhushan B, Nejak-Bowen K. Inhibiting Wnt Signaling Reduces Cholestatic Injury by Disrupting the Inflammatory Axis. Cell Mol Gastroenterol Hepatol. 2023;16(6):895-921. doi: 10.1016/j.jcmgh.2023.08.004. Epub 2023 Aug 12. PMID: 37579970; PMCID: PMC10616556. 6: Liang X, Li C, Song J, Liu A, Wang C, Wang W, Kang Y, Sun D, Qian J, Zhang X. HucMSC-Exo Promote Mucosal Healing in Experimental Colitis by Accelerating Intestinal Stem Cells and Epithelium Regeneration via Wnt Signaling Pathway. Int J Nanomedicine. 2023 May 25;18:2799-2818. doi: 10.2147/IJN.S402179. PMID: 37256205; PMCID: PMC10226545. 7: Lu A, Gu R, Chu C, Xia Y, Wang J, Davis DR, Liang W. Inhibition of Wnt/β-catenin signaling upregulates Nav 1.5 channels in Brugada syndrome iPSC-derived cardiomyocytes. Physiol Rep. 2023 May;11(10):e15696. doi: 10.14814/phy2.15696. PMID: 37226398; PMCID: PMC10209518. 8: Ling Y, Li J, Zhou L. Smoking-related epigenetic modifications are associated with the prognosis and chemotherapeutics of patients with bladder cancer. Int J Immunopathol Pharmacol. 2023 Jan-Dec;37:3946320231166774. doi: 10.1177/03946320231166774. PMID: 37011378; PMCID: PMC10074629. 9: Zhao Z, Liu H, Li Y, Tian J, Deng S. Retracted: Wnt-C59 Attenuates Pressure Overload-Induced Cardiac Hypertrophy via Interruption of Wnt Pathway. Med Sci Monit. 2023 Feb 9;29:e939725. doi: 10.12659/MSM.939725. PMID: 36756838; PMCID: PMC9926778. 10: Li F, Lun D, Liu D, Jia Z, Zhu Z, Liu Z, Li X. Melatonin activates mitochondrial unfolded protein response to preserve osteogenic potential of senescent BMSCs via upregulating PDI-6. Biochimie. 2023 Jun;209:44-51. doi: 10.1016/j.biochi.2023.01.015. Epub 2023 Jan 26. PMID: 36708867. 11: Ries A, Flehberger D, Slany A, Pirker C, Mader JC, Mohr T, Schelch K, Sinn K, Mosleh B, Hoda MA, Dome B, Dolznig H, Krupitza G, Müllauer L, Gerner C, Berger W, Grusch M. Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin. J Exp Clin Cancer Res. 2023 Jan 23;42(1):27. doi: 10.1186/s13046-022-02582-0. PMID: 36683050; PMCID: PMC9869633. 12: Hu J, Yang K, Zhao Y, Wei Z, Yang L, Gao R, Wu Y, Xu L, Xu S, Hu K, Sun A, Ge J. Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway. J Med Genet. 2022 Dec;59(12):1139-1149. doi: 10.1136/jmedgenet-2021-108396. Epub 2022 Jun 14. PMID: 35701104. 13: Yang J, Xu Y, Xue X, Zhang M, Wang S, Qi K. MicroRNA-26b regulates BMSC osteogenic differentiation of TMJ subchondral bone through β-catenin in osteoarthritis. Bone. 2022 Sep;162:116448. doi: 10.1016/j.bone.2022.116448. Epub 2022 May 23. PMID: 35618240. 14: Nijak A, Simons E, Vandendriessche B, Van de Sande D, Fransen E, Sieliwończyk E, Van Gucht I, Van Craenenbroeck E, Saenen J, Heidbuchel H, Ponsaerts P, Labro AJ, Snyders D, De Vos W, Schepers D, Alaerts M, Loeys BL. Morpho-functional comparison of differentiation protocols to create iPSC-derived cardiomyocytes. Biol Open. 2022 Feb 15;11(2):bio059016. doi: 10.1242/bio.059016. Epub 2022 Feb 23. PMID: 35195246; PMCID: PMC8890088. 15: Lu C, Lin X, Yamashita J, Xi R, Zhou M, Zhang YV, Wang H, Margolskee RF, Koo BK, Clevers H, Matsumoto I, Jiang P. RNF43/ZNRF3 negatively regulates taste tissue homeostasis and positively regulates dorsal lingual epithelial tissue homeostasis. Stem Cell Reports. 2022 Feb 8;17(2):369-383. doi: 10.1016/j.stemcr.2021.12.002. Epub 2022 Jan 6. PMID: 34995498; PMCID: PMC8828551. 16: Liu Z, Kuna VK, Xu B, Sumitran-Holgersson S. Wnt ligands 3a and 5a regulate proliferation and migration in human fetal liver progenitor cells. Transl Gastroenterol Hepatol. 2021 Oct 25;6:56. doi: 10.21037/tgh.2020.01.12. PMID: 34805578; PMCID: PMC8573361. 17: Torres VI, Barrera DP, Varas-Godoy M, Arancibia D, Inestrosa NC. Selective Surface and Intraluminal Localization of Wnt Ligands on Small Extracellular Vesicles Released by HT-22 Hippocampal Neurons. Front Cell Dev Biol. 2021 Oct 13;9:735888. doi: 10.3389/fcell.2021.735888. PMID: 34722516; PMCID: PMC8548728. 18: Bhattacharya D, Zhong J, Tavakoli S, Kabla A, Matsudaira P. Strain maps characterize the symmetry of convergence and extension patterns during zebrafish gastrulation. Sci Rep. 2021 Sep 29;11(1):19357. doi: 10.1038/s41598-021-98233-z. PMID: 34588480; PMCID: PMC8481280. 19: Godoy JA, Espinoza-Caicedo J, Inestrosa NC. Morphological neurite changes induced by porcupine inhibition are rescued by Wnt ligands. Cell Commun Signal. 2021 Aug 16;19(1):87. doi: 10.1186/s12964-021-00709-y. PMID: 34399774; PMCID: PMC8369806. 20: Jang J, Song J, Sim I, Kwon YV, Yoon Y. Wnt-Signaling Inhibitor Wnt-C59 Suppresses the Cytokine Upregulation in Multiple Organs of Lipopolysaccharide- Induced Endotoxemic Mice via Reducing the Interaction between β-Catenin and NF- κB. Int J Mol Sci. 2021 Jun 10;22(12):6249. doi: 10.3390/ijms22126249. PMID: 34200709; PMCID: PMC8230366.