Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Wnt signalling pathway plays a key role in the development of CSC(Cancer stem cell) and it may be a significant step in the development of a large number of tomours. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. [show the full text]
Wnt/beta-catenin inhibitors/activators
Other Stem Cells & Wnt Inhibitors
| Cat.No. | Product Name | Information | Product Use Citations | Product Validations |
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| S7086 | IWR-1-endo | IWR-1-endo (endo-IWR 1, IWR-1) is a Wnt pathway inhibitor with an IC50 of 180 nM in L-cells expressing Wnt3A, induces Axin2 protein levels and promotes β-catenin phosphorylation by stabilising Axin-scaffolded destruction complexes. |
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| S8968 | PRI-724 (Foscenvivint) | Foscenvivint (PRI-724) is a potent and specific inhibitor that disrupts the interaction of β-catenin and CBP. |
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| S7085 | IWP-2 | IWP-2 is an inhibitor of Wnt processing and secretion with IC50 of 27 nM in a cell-free assay, selective blockage of Porcn-mediated Wnt palmitoylation, does not affect Wnt/β-catenin in general and displays no effect against Wnt-stimulated cellular responses. IWP-2 specifically inhibits CK1δ. |
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| S0733 | Tegatrabetan (BC-2059) | Tegatrabetan (BC-2059, Tegavivint), an antagonist of β-Catenin, disrupts the binding of β-catenin with the scaffold protein transducin β-like 1 (TBL1) and proteasomal degradation, leading to declines in the nuclear levels of β-catenin. |
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| S3842 | Isoquercitrin | Isoquercitrin (Hirsutrin, 3-Glucosylquercetin, Quercetin 3-o-glucopyranoside), a flavonoid compound with anticancer activity isolated from Bidens bipinnata L, is an inhibitor of Wnt/ A-catenin that acts downstream of the A-catenin nuclear translocation. |
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| S2662 | ICG-001 | ICG-001 antagonizes Wnt/β-catenin/TCF-mediated transcription and specifically binds to CREB-binding protein (CBP) with IC50 of 3 μM, but is not the related transcriptional coactivator p300. ICG-001 induces apoptosis. |
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| S1263 | CHIR-99021 (Laduviglusib) | Laduviglusib (CHIR-99021, CT99021) is a GSK-3α and GSK-3β inhibitor with IC50 values of 10 nM and 6.7 nM, respectively. It does not exhibit cross-reactivity against cyclin-dependent kinases (CDKs) and shows a 350-fold selectivity toward GSK-3β compared to CDKs. This compound functions as a Wnt/β-catenin activator and induces autophagy. |
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| S2924 | Laduviglusib (CHIR-99021) Hydrochloride | Laduviglusib (CHIR-99021; CT99021) HCl is hydrochloride of CHIR-99021, which is a GSK-3α/β inhibitor with IC50 of 10 nM/6.7 nM; CHIR-99021 shows greater than 500-fold selectivity for GSK-3 versus its closest homologs Cdc2 and ERK2. CHIR-99021 is a potent pharmacological activators of the Wnt/beta-catenin signaling pathway. CHIR-99021 significantly rescues light-induced autophagy and augments GR, RORα and autophagy-related proteins. |
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| S1180 | XAV-939 | XAV-939 (NVP-XAV939) selectively inhibits Wnt/β-catenin-mediated transcription through tankyrase1/2 inhibition with IC50 of 11 nM/4 nM in cell-free assays, regulates axin levels and does not affect CRE, NF-κB or TGF-β. |
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| S5992 | Heparan Sulfate | Heparan sulfate (HS, Heparitin sulfate, Alpha-idosane, HHS 5, N-Acetylheparan Sulfate, Suleparoid, Tavidan), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. Heparan sulfate influences the binding affinity of intestinal epithelium cells (IECs) to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury. |
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The Wnt/β-catenin signalling pathway is an important mechanism of study for researchers of human diseases as it plays a role in oncology when overactivated, however, reduced signalling of this pathway also results in abnormal bone development and neurodegenerative illnesses. Depending on the indication of use, development of inhibitors or activators of the Wnt/β-catenin signalling pathway is an important area of focus.
Normally, regulation of the Wnt/β-catenin signalling pathway occurs by a large protein assembly called the β-catenin destruction complex that maintains low concentrations of β-catenin in the cytoplasm, and consequently in the nucleus. The β-catenin destruction complex is comprised of glycogen synthase kinase 3 (GSK3α/ GSK3β), casein kinase Iα (CKIα), Axin1/Axin2 scaffolding, and adenomatous polyposis coli (APC) – a tumor suppressor protein. Recruitment of β-catenin to the destruction complex leads to the phosphorylation of β-catenin N-terminus residues by CKIα and GSK3, following which ubiquitination and degradation events occur. Sequestering β-catenin at several N-terminal serine and threonine residues to the β-catenin destruction complex are Axin and APC. Similarly, it is believed these constituents of the β-catenin destruction complex regulate β-catenin efflux from the nucleus. The low concentration of β-catenin in the cell restricts β-catenin to the essential role of cadherin-mediated cell adhesion. An additional mechanism controlling the expression of Wnt signalling in the cell involves the inhibition of Wnt specific gene transcription by the T-cell factor (TCF) family of proteins.[1]
Activation of the Wnt/β-catenin signalling pathway is signified by the formation of a “Wnt signalosome” – a large protein complex that develops following the recognition of Wnt protein on the cell surface by a set of proteins called the seven-pass transmembrane Frizzled (Fz) family and its co-receptor, low density lipoprotein receptor related protein (LRP5/LRP6).ii The Wnt signalosome inhibits the activity of the β-catenin destruction complex by recruiting several components of the destruction complex to the membrane. As a consequence, the buildup of β-catenin’s unphosphorylated form results in the cytoplasm and subsequently in the nucleus. It is in the nucleus where rising concentrations of β-catenin combine with TCF proteins to transform this protein from an inhibitory protein to an activator of Wnt-signalling pathway by encouraging the transcription of the Wnt-responsive gene.[1]
Among cancer research, Wnt/β-catenin signalling is an area of focus since loss-of-function mutations in the APC gene results in β-catenin stabilization. Deletions within a chromosomal region containing the APC gene is understood to be associated with a hereditary disease known as familial adenomatous polyposis that yield intestinal polyps in large numbers that ultimately gives rise to tumors. Alternatively, mutations that promote gain-of-function of the APC gene inhibit the β-catenin destruction complex from limiting β-catenin concentrations in the cell. Additionally, some cancers have been correlated to a loss of Axin1 or Axin2 function. Overexpression of the Wnt/ β-catenin signalling pathway results in the constitutive activation of c-myc, and is most commonly linked to colorectal cancer.[2]
Since the Wnt/β-catenin signalling pathway plays a critical role in cancer, clinical research has yielded several new targets that may positively influence Wnt/β-catenin signalling where its absence is related to disease. Potential new drug targets include two lipid kinases that were found with the accumulation of β-catenin among HEK293T cells transfected with short inhibitory RNAs (siRNAs) targeting human kinases, these include: (1) phosphatidylinositol 4-kinase type IIα (PI4KIIα), and (2) phosphatidylinositol-4-phosphate 5-kinase type Iβ (PIP5Kiβ). Additionally, three human homologs of Drosophila PAR-1 can also provide useful drug targets as these elements activate Wnt/β-catenin signalling pathway as well.[2]
There are many enzymes involved in the Wnt/β-catenin signalling pathway and knowing whether activation or repression is best suited will determine the molecular strategy to explore for therapeutic benefit.
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