Inhibitors of the Wnt signaling and their effects in cancer
| Targets and Functions | Agent Name | Functional Effects in Cancer | Development Stage | Reference |
|---|---|---|---|---|
| Small molecule tankyrase (TNKS1/2) inhibitors, stabilizing AXIN1/2 | IWRs | Discovery | Chen et al., 2009 | |
| XAV939 | Inhibited colony formation of colorectal cancer cell line DLD-1. | Huang et al., 2009 | ||
| WIKI4 | James et al., 2012 | |||
| NVP-TNKS656 | Shultz et al., 2013 | |||
| JW67, JW74 | Both compounds suppressed in vitro proliferation of colorectal cancer cell line SW480; JW74 reduced SW480 in vivo tumor growth and adenoma formation in ApcMin mice. | Preclinical | Waaler et al., 2011 | |
| JW55 | Suppressed in vitro proliferation of SW480; decreased adenoma formation in conditional Apc knockout mice. | Waaler et al., 2012 | ||
| G007-LK | Suppressed in vitro colony formation and in vivo tumor growth of colorectal cancer cell lines COLO-320DM and SW403 and spheroid formation of ApcMin mouse intestinal adenoma. | Lau et al., 2013 | ||
| K-756 | Suppressed in vitro proliferation of COLO-320DM and SW403; showed dose-dependent inhibition of Wnt signaling in DLD-1 xenografts. | Okada-Iwasaki et al., 2016 | ||
| Small molecule CK1α activators, promoting β-catenin degradation | Pyrvinium | Suppressed in vitro proliferation of colorectal cancer cell lines SW480, DLD-1, SW620, HCT116, and HT29; reduced adenoma formation in ApcMin mice. | Preclinical | Thorne et al., 2010; Li et al., 2014; |
| SSTC3 | Suppressed intestinal organoid formation from ApcMin mice and Apc knockout mice; reduced adenoma formation in ApcMin mice; suppressed in vitro colony formation of HT29, SW403, and HCT116 and in vivo tumor growth of HCT116; suppressed tumor organoid formation from three patient colorectal tumors and in vivo growth of xenografts. | Li et al., 2017 | ||
| Small molecule inhibitors blocking β-catenin/TCF interaction | iCRT3, iCRT5, and iCRT14 | iCRTs led to cell cycle arrest in HCT116 and HT29; iCRT3 suppressed in vitro growth of primary human colon cancer specimens; iCRT14 reduced HCT116 and HT29 xenograft growth. | Preclinical | Gonsalves et al., 2011 |
| Small molecule inhibitors blocking β-catenin/CBP interaction | ICG-001 | Suppressed in vitro growth and led to apoptosis in SW480 and HCT116; suppressed in vivo growth of SW620 xenografts; reduced adenoma formation in ApcMin mice; suppressed in vitro growth of pancreatic cancer cell lines AsPC-1, L3.6pl, MIA PaCa-2, and PANC-1; improved survival of AsPC-1 orthotopic xenograft-bearing mice. | Preclinical | Emami et al., 2004; Arensman et al., 2014 |
| PRI-724 | The active enantiomer of ICG-001; entered Phase 1 and 2 clinical trials for treating advanced cancers. | Phase 1 and 2 clinical trials | ClinicalTrials.gov NCT01764477, NCT01302405, NCT01606579, NCT02413853 | |
| Small molecule inhibitor blocking β-catenin/p300 interaction | Windorphen | Suppressed in vitro proliferation of colorectal cancer cell lines SW480 and RKO and prostate cancer cell lines DU145 and PC3. | Discovery | Hao et al., 2013 |
| Small molecule PORCN inhibitors, blocking Wnt secretion | IWPs | Discovery | Chen et al., 2009 | |
| C59 | Inhibited MMTV-Wnt1 tumor growth in vivo. | Preclinical | Proffitt et al., 2013 | |
| LGK974 | Induced regression of MMTV-WNT1 tumors; inhibited in vitro colony formation of head and neck cancer cell line HN30 and RNF43-mutant pancreatic cancer cell lines Patu8988S and HPAF-II; inhibited in vivo tumor growth in xenografts of HN30 and RNF43-mutant pancreatic cancer cell lines Capan2 and HPAF-II; entered Phase 1 and 2 clinical trials for treating cancers. | Phase 1 and 2 clinical trials | Jiang et al., 2013; Liu et al., 2013; ClinicalTrials.gov NCT01351103, NCT02278133, NCT02649530 | |
| ETC-159 | Inhibited in vitro colony formation of teratocarcinoma cell lines PA-1 and RNF43-mutant pancreatic and ovarian cancer cell lines HPAF-II, AsPC-1, and MCAS; suppressed in vivo tumor growth in xenografts of HPAF-II, AsPC-1, teratocarcinoma cell lines PA-1 and NCCIT, and patient-derived colorectal tumor xenografts with RSPO3 fusions; entered Phase 1 clinical trial for treating advanced cancers. | Phase 1 clinical trial | Madan et al., 2016a; ClinicalTrials.gov NCT02521844 | |
| RXC004 | Suppressed in vivo tumor growth of Capan2 xenografts; entered Phase 1 clinical trial for treating advanced cancers. | Phase 1 clinical trial | Bhamra et al., 2017; ClinicalTrials.gov NCT03447470 | |
| CGX1321 | Suppressed in vivo tumor growth of patient-derived gastric and colorectal tumor xenografts with RSPO2 fusions; entered Phase 1 clinical trial for treating advanced cancers. | Phase 1 clinical trial | Li et al., 2018; ClinicalTrials.gov NCT03507998, NCT02675946 | |
| Decoy Wnt receptor | Ipafricept (OMP-54F28) | Suppressed in vivo tumor growth of patient-derived hepatocellular carcinoma, pancreatic and ovarian cancer xenografts, and decreased the cancer stem cell frequency; entered Phase 1 clinical trials for treating advanced cancers; in a Phase 1 clinical trial, two desmoid tumor, and a patient with germ cell cancer treated with Ipafricept experienced stable disease for >6 mo. | Phase 1 clinical trials | Jimeno et al., 2017; ClinicalTrials.gov NCT02069145, NCT02092363, NCT02050178, NCT01608867 |
| Anti-Frizzled1,2,5,7,8 antibody | Vantictumab (OMP-18R5) | Suppressed in vivo tumor growth of patient-derived colorectal, breast, lung, and pancreatic tumor xenografts and PA-1 xenografts; decreased the cancer stem cell frequency; entered Phase 1 clinical trials for treating cancers. | Phase 1 clinical trials | Gurney et al., 2012; ClinicalTrials.gov NCT01345201, NCT02005315, NCT01957007, NCT01973309 |
| Anti-Frizzled5,8 antibodies | IgG-2919, IgG-2921 | Both antibodies suppressed in vitro proliferation of RNF43-mutant pancreatic cancer cell lines HPAF-II, Patu8988S, and AsPC-1, and led to cell cycle arrest; IgG-2912 suppressed in vivo tumor growth of HPAF-II and AsPC-1 xenografts and organoid formation of RNF43-mutant colorectal cancers. | Preclinical | Steinhart et al., 2017 |
| Anti-LRP6 antibodies | A7-IgG, B2-IgG | A7-IgG specifically inhibited tumor growth of MMTV-Wnt1 xenografts; B2-IgG specifically inhibited tumor growth of MMTV-Wnt3 xenografts. | Preclinical | Ettenberg et al., 2010 |
| Anti-RSPO antibodies | Anti-RSPO1 antibody, anti-RSPO2 antibody, anti-RSPO3 antibodies | Suppressed in vivo tumor growth of patient-derived colorectal, lung, and ovarian tumor xenografts with corresponding RSPO overexpression; Anti-RSPO3 antibody (OMP-131R10) has entered Phase 1 clinical trial for treating advanced solid tumors and metastatic colorectal cancers. | Preclinical, phase 1 clinical trial (OMP-131R10) | Chartier et al., 2016; Storm et al., 2016; ClinicalTrials.gov NCT02482441 |