Table 1.
Therapeutic targets and inhibitors that are evaluated in clinical studies regarding cancers and Wnt signaling.
| Target | Compound Name | Cancer Model | Description | Activity (IC50) | Clinical Phase | Reference/Clinicaltrials.gov |
|---|---|---|---|---|---|---|
| Small-molecule compounds | ||||||
| PORCN | WNT974 (LGK974) | BRAF mutant colorectal cancer | In combination with cetuximab and LGX818 | 0.4 nM | Ib/II | NCT02278133 |
| Primary ovarian cancer (OV-7 and OV-14 cell lines) | In combination with carboplatin | 1.14 µM, 1.76 µM | NA | [219] | ||
| Head and neck squamous carcinoma | Reduced axin 2 mRNA level | 0.3 nM | II | NCT02649530 | ||
| Triple-negative breast cancer | In combination with buparlisib. Dual targeting of the PI3K and Wnt pathways | NA | I |
NCT01351103 [220,221,222] |
||
| Melanoma | Antitumor activity | NA | ||||
| Pancreatic adenocarcinoma | Reduces the expression of Axin2 | NA | ||||
| ETC-159 (ETC-1922159) | Solid tumors | Induces tumor regression | NA | I | NCT02521844 | |
| Colorectal cancer with R-Spondin translocations | Prevents tumor regrowth by inducing irreversible cellular differentiation | 2.9 nM | Preclinical | [215] | ||
| C59 (WNT C59) | Mammary tumors in mice | Inhibits Wnt-1–promoted tumor growth in mice | 74 pM | Preclinical | [213] | |
| Nasopharyngeal carcinoma in mice | Inhibits NPC subcutaneous tumor growth | NA | NA | [223] | ||
| Intestinal neoplasia in mice | Inhibits RNF43 & ZNRF43 mutant intestinal epithelium | NA | NA | [224] | ||
| IWP-2 | Colorectal cancer | Suppression of Wnt ligand production | 27 nM | Preclinical | [212,225] | |
| RXC-004 | Solid tumors | Reduces tumor sizes | NA | NA | [214] | |
| TANKs | XAV939 (XAV) | Colorectal cancer | Induces axin stabilization and inhibits colony formation of DLD-1 cells | 11 nM (TNKS1), 4 nM (TNKS2) | Preclinical | [226] |
| Prostate cancer | Attenuates β-catenin translocation to the nucleus | NA | [227] | |||
| Breast cancer cells | Decreases Wnt-3a promoted cell migration in MDA-MB-231 cells | 1.5 µM | [228] | |||
| Lung adenocarcinoma | Attenuated the colony formation, proliferation, and migration of A549 cells | NA | [229] | |||
| E7449 (2X-121) | Advanced ovarian cancer | Anti-tumor activity | 50–100 nM | II | NCT03878849 | |
| Triple-negative breast cancer | In combination with carboplatin and paclitaxel | NA | NA | NCT01618136 | ||
| AZ1366 | Non–small cell lung cancer | Decreases tumor growth in combination with gefitinib | NA | Preclinical | [230] | |
| JW55 | Colorectal cancer | Reduces Wnt signaling and tumor cell growth in SW480 cells | 1.9 µM (TNKS1), 0.83 µM (TNKS2) | Preclinical | [231] | |
| NVP-TNKS656 | Colorectal cancer | Suppresses cancer growth in APC-mutant Patient-derived xenograft models | 6 nM (TNKS2) | Preclinical | [232] | |
| GOO7-LK | Colorectal cancer | Inhibits tumor growth in APC-mutant CRC xenograft models | 46 nM (TNKS1), 25 nM (TNKS2) | Preclinical | [233] | |
| IWR-1 | Osteosarcoma | Decreases tumor growth in combination with doxorubicin | 0.18 µM | Preclinical | [212,234] | |
| JW74 | Colorectal cancer | Downregulates Wnt target genes | 790 nM | Preclinical | [235] | |
| TNKSi49 | Colorectal cancer | Suppresses tumor growth | 0.3 nM | NA | [236] | |
| WIKI4 | Multiple cell lines | Inhibits TNKS 2 activity | 15 nM (TNKS2) | NA | [237] | |
| β-Catenin | PRI-724 (ICG-001) | Pancreatic cancer | Inhibits tumor growth | 3 µM | Ib | NCT01764477 |
| Osteosarcoma | Attenuates cell proliferation in 143B and SJSA-1 cells | NA | Preclinical | [238] | ||
| Acute myeloid leukemia and Chronic myeloid leukemia | Inhibits metastasis | NA | I/II | NCT01606579 | ||
| Colorectal cancer | In combination with mFOLFOX6 and bevacizumab | NA | II | NCT02413853 | ||
| CWP232228 | Breast cancer stem cells | Inhibits tumor growth by attenuating β-catenin–driven transcription | 0.8 µM | Preclinical | [239] | |
| CWP232291 (CWP 291) | Acute myeloid leukemia and chronic myeloid leukemia | Induces β-catenin degradation | 273 nM | I |
NCT01398462 [240] |
|
| BC2059 (Tegavivint) | Acute myeloid leukemia | Reduces β-catenin level | NA | Preclinical | [241] | |
| Desmoid tumor | Primary or recurrent desmoid tumor | NA | I | NCT03459469 | ||
| LF3 | Colorectal cancer | Reduces tumor growth | <2 µM | Preclinical | [242] | |
| MSAB | Colorectal cancer | Induces β-catenin degradation | <6 µM | Preclinical | [243] | |
| SAH-BCL9 | Colorectal cancer | Inhibits tumor cell migration and proliferation | 135 nM | Preclinical | [244] | |
| 2,4-diamino-quinazoline | Colorectal cancer | Inhibits the β-catenin–TCF4 pathway | 0.22 µM | Preclinical | [245] | |
| PNU-74654 | Breast cancer | It enhances apoptosis and reduces β-catenin accumulation and cell proliferation. Used in combination with 5-fluorouracil | 122 µM | NA | [246] | |
| iCRT3 | Triple-negative breast cancer | Inhibits the β-catenin nuclear activity | 8.2 nM | Preclinical | [247] | |
| PKF115-584 | Colorectal cancer, Hepatocellular cancer | Inhibits tumor cell proliferation and disrupts β-catenin–Tcf complex | 3.2 µM | Preclinical | [248,249] | |
| 0.8 µM | ||||||
| PKF118-310 | ||||||
| CGP049090 | 8.7 µM | |||||
| AV-65 | Multiple myelomas | Inhibits the growth of MM cells in the mouse model | NA | Preclinical | [250] | |
| CCT036477 | Colorectal cancer | Inhibits tumor growth in β-catenin mutant mice | NA | Preclinical | [251] | |
| DVL | 3289-8625 | Prostate cancer | Decreases tumor growth in PC-3 cells | 12.5 µM | NA | [252] |
| FJ9 | Lung cancer and melanoma cells | Reduces tumor cell growth | Ki = 29µM | NA | [253] | |
| Antibodies | ||||||
| FZDs | Vantictumab (OMP18R5) | Breast cancer | In combination with Paclitaxel | NA | I | NCT01973309 |
| Pancreatic cancer | In combination with nab-paclitaxel and gemcitabine | NCT02005315 | ||||
| FZD8CRD (F8CRDhFc) | Teratocarcinomas | Inhibits tumor growth | Preclinical | [254] | ||
| OMP-54F28 (Ipafricept) | Ovarian cancer | In combination with paclitaxel and carboplatin | I | NCT02092363 | ||
| Hepatocellular cancer | In combination with sorafenib | NCT02069145 | ||||
| Pancreatic cancer | In combination with nab-paclitaxel and gemcitabine | NCT02050178 | ||||
| IgG-2919 (Anti-FZD5 mAb) | Pancreatic cancer | Inhibits tumor growth | Preclinical | [200] | ||
| OTSA101 (OTSA101-DTPA-90Y) | Synovial sarcoma | Antitumor activity | I |
NCT01469975 [201] |
||
| MC-Val-Cit-PAB-MMAE | Gastric cancer | Preclinical | [255] | |||
| R-spondin3 | OMP-131R10 (Rosmantuzumab) | Colorectal cancer | Inhibits tumor growth | NA | I |
NCT02482441 [256] |
APC, Adenomatous polyposis coli; CRC, Colorectal cancer; DVL, Dishevelled; FZDs, Frizzleds; IC50, Inhibitory concentration; IWP, Inhibitors of WNT production; Ki, Kinetic Inhibitor; NA, Not applicable; NPC, Nasopharyngeal carcinoma; PI3K Pathway, Phosphoinositide 3-kinase pathway; PORCN, Porcupine; Rnf43, RING finger protein 43; TANKs, Tankyrases; TNBC, Triple-negative breast cancer; Znrf3, zinc RING finger protein 3.