Table 1.
Currently Known Inhibitors of the Canonical WNT Signaling Pathway
| Molecular Targets | Inhibitors | Anti-WNT and Anticancer Activities | Stage of Development | References |
|---|---|---|---|---|
| WNTs | Antibodies | WNT-blocking antibodies were developed and shown to inhibit proliferation and induce apoptosis in different cancers | preclinical | 21, 262-265 |
| SFRPs/WIF | overexpress naturally occurring antagonists of WNT ligands | 266-268 | ||
| SFRP peptides | SFRP1 and SFRP1-derived peptides can delay HCT116 xenograft tumor formation | 266 | ||
| DNA demethylation agents | use DNA demethylation agents to reverse hypermethylation of SFRP promoters | 273 | ||
| FZDs | OMP18R5 | humanized monoclonal anti-body that binds to FZD1, FZD2, FZD5, FZD7 and FZD8 | Phase Ia | 28 |
| FZD8CRD | fusion protein consisting of the Fc region of IgG fused to the extracellular domain of FZD8 | preclinical | 270-271 | |
| DVL | NSC668036 | inhibits the DVL PDZ domain, not reported in cancer | Preclinical | 274-276 |
| 3289-8625 | inhibits the growth of prostate cancer PC-3 cells | |||
| FJ9 | disrupts the interaction between FZD7 and the PDZ domain of DVL, induces apoptosis and inhibits H460 lung cancer growth | |||
| sulindac | inhibits proliferation of lung cancer A549 cells | FDA Approved | 300, 301 | |
| TANKs | XAV-939 | inhibits colony formation of β-catenin-dependent DLD-1 cells | Preclinical | 277 |
| JW55 | decreases canonical Wnt signaling in SW480 and HCT-15 colon carcinoma cell lines; reduces cell cycle progression and proliferation in SW480 cells in vitro | 279 | ||
| G007-LK | suppresses APC mutation-driven colorectal tumor growth | 280 | ||
| IWR-1 | inhibits L-cells expressing Wnt3A | 278 | ||
| PORC | IWP | inhibits colorectal cancer cells invasion by WISP2 | Preclinical | 278 |
| LGK-974 | inhibits growth of Mouse MMTV-WNT1 tumor model and human head and neck squamous cell carcinoma model | Phase I clinical trial | 259, 282 | |
| WNT C59 | PORC inhibitor with 10-fold therapeutic dose over toxic dose | Preclinical | 283 | |
| Activation of CK1α to promote β-catenin degradation | Pyrvinium | Pyrvinium synergizes with 5-fluorouracil in mediating the apoptosis of SW620 colorectal cancer cells and inhibits the proliferation of SW480 and HCT116 cells. | Preclinical | 317 |
| β-catenin/TCF interaction | iCRT3, iCRT5, and iCRT14 | reduced the growth of colorectal cancer cells | Preclinical | 288 |
| PKF115-584, CGP049090 and PKF118-310 | inhibit the growth of HCC cells in xenografts | 284-286 | ||
| 2,4 diamino-quinazoline | inhibitor lead of the β-catenin-TCF4 pathway | 287 | ||
| PNU-74654 | a druglike β-catenin-TCF antagonist | 289 | ||
| BC21 | an organo-copper complex as the top-ranked compound that can bind to the armadillo repeat | 290 | ||
| AV-65 | inhibits progression of multiple myeloma in a mouse model | 291 | ||
| stapled peptides | potent inhibitors to target the β-catenin-BCL9 interface and and the β-catenin-TCF4 interface | 292, 293 | ||
| β-catenin/CBP interaction | ICG-001 | decreases xenograft growth of SW620 colon carcinoma cells | Preclinical | 294, 295 |
| PRI-724 | downregulates survivin (BIRC5) expression in circulating tumour cells, supresses growth of refractory pancreatic cancer | Phase Ia | 259, 302 | |
| β-catenin/TCF-regulated transcription; signal crosstalk; non-specific or overlapping targeting | CCT036477, CCT070535, and CCT031374 | Inhibits the growth of SW480 and HCT116 colorectal cell lines | Preclinical | 26 |
| OSU03012 | PDK1 inhibitor OSU03012 inhibits the growth of various medulloblastoma cell lines | 307 | ||
| Celecoxib | induces apoptosis in cervical cancer cells | FDA Approved | 303,304 | |
| Imatinib | tyrosine kinase inhibitor that inihibits TCF/β-catenin activity | FDA Approved | 305 | |
| PHA665752 | c-MET inhibitor shown to inhibit WNT/β-catenin signaling | Preclinical | 306 | |
| OSU03012 | PDK1 inhibitor to suppress medulloblastoma xenograft tumors | 307 | ||
| IQ-1 | protein phosphatase 2A (PP2A) regulatory subunits PR72 and PR130 shown to maintain pluripotency in murine ES cells in a WNT-dependent manner | 296 | ||
| ID-8 | dual specificity YAK1 related kinases (DYRKs) shown to allow for long-term WNT-mediated maintenance of human ES cells | 297 | ||
| Retinoic acids | induces Disabled homolog 2 (DAB2) | 308 | ||
| Vitamin D | induces DKK1 and DKK4 | 308 | ||
| Natural products | quercetin, epigallocatechin-3-gallate (EGCG), curcumin, resveratrol, ginsenoside Rg3, and tetrandrine | 308-314 | ||
| Silibinin | suppressing LRP6 expression in human prostate and breast cancer cells | 315 | ||
| Rottlerin | shown to induce LRP6 degradation and suppress both WNT/β-catenin and mTORC1 signaling pathways in prostate and breast cancer cells | 316 | ||
| Niclosamide | promoting FZD1 endocytosis, down-regulating DVL2 protein, and inhibiting WNT3A-stimulated β-catenin stabilization and LEF/TCF activity; anticancer activity in WNT-independent manner as well | FDA Approved | 319-325 | |
| Salinomycin | blocking the phosphorylation of LRP6 and induce its degradation | Preclinical | 326 | |
| Monensin | a potent blocker of WNT-induced transcription and to inhibit the progression of intestinal tumors without any sign of toxicity on normal mucosa | 327 |