The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin signal by preventing poly ADP-ribosylation-dependent degradation of AXIN, a negative regulator of Wnt/β-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small-molecule inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that RK-287107 is a promising lead compound for the development of novel tankyrase inhibitors as anticancer agents.
Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer.J Med Chem. 2020 Apr 23;63(8):4183-4204. doi: 10.1021/acs.jmedchem.0c00045. Epub 2020 Apr 1. J Med Chem. 2020. PMID: 32202790
RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model.Cancer Sci. 2018 Dec;109(12):4003-4014. doi: 10.1111/cas.13805. Epub 2018 Oct 20. Cancer Sci. 2018. PMID: 30238564 Free PMC article.
The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase.Mol Cancer Ther. 2016 Jul;15(7):1525-34. doi: 10.1158/1535-7163.MCT-15-0938. Epub 2016 Apr 25. Mol Cancer Ther. 2016. PMID: 27196752
Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding.Br J Pharmacol. 2017 Dec;174(24):4611-4636. doi: 10.1111/bph.14038. Epub 2017 Nov 5. Br J Pharmacol. 2017. PMID: 28910490 Free PMC article. Review.
Tankyrase as a Novel Molecular Target in Cancer and Fibrotic Diseases.Curr Drug Targets. 2017;18(10):1214-1224. doi: 10.2174/1389450117666160715152503. Curr Drug Targets. 2017. PMID: 27425647 Review.