- •Tankyrase1/2 inhibitor STP1002 has anti-tumour activity.
- •STP1002 stabilises AXINs in adenomatous polyposis coli-mutated colorectal cancer cell lines and in vivo.
- •STP1002 antagonises the Wnt pathway in adenomatous polyposis coli-mutated colorectal cancer cell lines and in vivo.
- •STP1002 showed favourable pharmacokinetic profiles in vitro and in vivo.
- •STP1002 showed no on-target toxicity in the gastrointestinal tract in various pre-clinical models.
Abbreviations:ADME (absorption, distribution, metabolism, and excretion), ANOVA (analysis of variance), APC (adenomatous polyposis coli), APCDD1 (adenomatous polyposis coli down-regulated 1), ASCL2 (achaete-scute family bHLH transcription factor 2), AUC (area under the plasma concentration–time curve), BID (bis in die (twice a day)), β-NAD+ (β-nicotinamide adenine dinucleotide), Cmax (maximum plasma concentration), CCND1 (cyclin D1), CK1α (casein kinase 1 α), CRC (colorectal cancer), FABP2 (fatty acid binding protein 2), GI (gastro intestinal), GSK3β (glycogen synthase kinase 3β), IP (intraperitoneal), KRT20 (keratin 20), LGR5 (leucine rich repeat containing G protein-coupled receptor 5), NKD1 (naked cuticle 1), PARP (members of the poly (ADP-ribose) polymerase), PK (pharmacokinetic), PD (pharmacodynamic), PDX (Patient-Derived Xenograft), PO (per os (by mouth)), PP2A (protein phosphatase 2A), QD (queque die (every day)), Tmax (time of maximum concentration), TNKS (tankyrase), TGI (tumour growth inhibition), TNFRSF19 (TNF receptor superfamily member 19), TFF3 (trefoil factor 3)
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
- Wnt signaling in cancer.Oncogene. 2017; 36: 1461-1473https://doi.org/10.1038/onc.2016.304
- Tankyrase inhibitors: potential treatment of hyperproliferative diseases.ACS Med Chem Lett. 2014; 5: 10-11https://doi.org/10.1021/ml400508g
- The Wnt signaling pathway in development and disease.Annu Rev Cell Dev Biol. 2004; 20: 781-810https://doi.org/10.1146/annurev.cellbio.20.010403.113126
- Targeting Wnt signaling in colon cancer stem cells.Clin Cancer Res. 2011; 17: 647-653https://doi.org/10.1158/1078-0432.CCR-10-1204
- Linking colorectal cancer to Wnt signaling.Cell. 2000; 103: 311-320https://doi.org/10.1016/s0092-8674(00)00122-7
- Tankyrase inhibitors as antitumor agents: a patent update (2013 - 2020).Expert Opin Ther Pat. 2021; : 1-17https://doi.org/10.1080/13543776.2021.1888929
- Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond beta-catenin and the destruction complex.Exp Mol Med. 2020; 52: 183-191https://doi.org/10.1038/s12276-020-0380-6
- Insights of tankyrases: a novel target for drug discovery.Eur J Med Chem. 2020; 207112712https://doi.org/10.1016/j.ejmech.2020.112712
- Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins.Cell Rep. 2015; 13: 524-532https://doi.org/10.1016/j.celrep.2015.09.014
- Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.Nature. 2009; 461: 614-620https://doi.org/10.1038/nature08356
- Novel binding mode of a potent and selective tankyrase inhibitor.PLoS One. 2012; 7e33740https://doi.org/10.1371/journal.pone.0033740
- The discovery and characterization of K-756, a novel wnt/beta-catenin pathway inhibitor targeting tankyrase.Mol Cancer Ther. 2016; 15: 1525-1534https://doi.org/10.1158/1535-7163.MCT-15-0938
- The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance.Oncotarget. 2016; 7: 28273-28285https://doi.org/10.18632/oncotarget.8626
- Tankyrase inhibition causes reversible intestinal toxicity in mice with a therapeutic index < 1.Toxicol Pathol. 2016; 44: 267-278https://doi.org/10.1177/0192623315621192
- A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice.Cancer Res. 2012; 72: 2822-2832https://doi.org/10.1158/0008-5472.CAN-11-3336
- RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model.Cancer Sci. 2018; 109: 4003-4014https://doi.org/10.1111/cas.13805
- A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors.Sci Rep. 2019; 9: 201https://doi.org/10.1038/s41598-018-36447-4
- Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor.J Med Chem. 2013; 56: 6495-6511https://doi.org/10.1021/jm400807n
- A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth.Cancer Res. 2013; 73: 3132-3144https://doi.org/10.1158/0008-5472.CAN-12-4562
- Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs.Int J Pharm. 2012; 438: 53-60https://doi.org/10.1016/j.ijpharm.2012.08.031
- Novel triazolopyrimidinone or triazolopyridinone derivatives, and use thereof.2016
- APC mutations as a potential biomarker for sensitivity to tankyrase inhibitors in colorectal cancer.Mol Cancer Ther. 2017; 16: 752-762https://doi.org/10.1158/1535-7163.MCT-16-0578
- Quantitative proteomic analysis of 2D and 3D cultured colorectal cancer cells: profiling of tankyrase inhibitor XAV939-induced proteome.Sci Rep. 2018; 813255https://doi.org/10.1038/s41598-018-31564-6
- Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.Nat Cell Biol. 2010; 12: 468-476https://doi.org/10.1038/ncb2048
- Evidence that fold-change, and not absolute level, of beta-catenin dictates Wnt signaling.Mol Cell. 2009; 36: 872-884https://doi.org/10.1016/j.molcel.2009.11.017
- Distinct colorectal cancer-associated APC mutations dictate response to tankyrase inhibition.Cancer Discov. 2019; 9: 1358-1371https://doi.org/10.1158/2159-8290.CD-19-0289
- Can we safely target the WNT pathway?.Nat Rev Drug Discov. 2014; 13: 513-532https://doi.org/10.1038/nrd4233
- Emerging cytokine networks in colorectal cancer.Nat Rev Immunol. 2015; 15: 615-629https://doi.org/10.1038/nri3896
- E7449: a dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling.Oncotarget. 2015; 6: 41307-41323https://doi.org/10.18632/oncotarget.5846
- Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth.Cancer Res. 2011; 71: 197-205https://doi.org/10.1158/0008-5472.CAN-10-1282
- Tankyrase inhibition blocks wnt/beta-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer.Clin Cancer Res. 2016; 22: 644-656https://doi.org/10.1158/1078-0432.CCR-14-3081
- AZ1366: an inhibitor of tankyrase and the canonical Wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition.Clin Cancer Res. 2017; 23: 1531-1541https://doi.org/10.1158/1078-0432.CCR-16-1179
- Reducing safety-related drug attrition: the use of in vitro pharmacological profiling.Nat Rev Drug Discov. 2012; 11: 909-922https://doi.org/10.1038/nrd3845
- Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage.Cell Commun Signal. 2021; 19: 31https://doi.org/10.1186/s12964-021-00712-3
- Discovery of novel spiroindoline derivatives as selective tankyrase inhibitors.J Med Chem. 2019; 62: 3407-3427https://doi.org/10.1021/acs.jmedchem.8b01888