A TNKS1/2 inhibitor
IC50: 1.9 μM (TNK S1); 0.83 μM (TNK S2)
Increased nuclear accumulation of β-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/b-catenin signaling therefore is an attractive strategy for anticancer drugs.
In vitro: In a previous study, the authors identified a novel small molecule inhibitor of the β-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the b-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the b-catenin destruction complex, followed by increased degradation of b-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of b-catenin [1].
In vivo: JW55 was reported to reduce XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. These findings provide a novel chemotype for targeting canonical Wnt/b-catenin signaling through inhibiting the PARP domain of TNKS1/2 [1].
Clinical trial: JW55 is currently in the preclinical development and no clinical trial is ongoing.
Reference:
[1] Waaler J, Machon O, Tumova L, Dinh H, Korinek V, Wilson SR, Paulsen JE, Pedersen NM, Eide TJ, Machonova O, Gradl D, Voronkov A, von Kries JP, Krauss S.? 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(11):2822-32.
Cell experiment: | A total of 1,000 SW480 or RKO cells are seeded in 96-well plates. The day after, the cell culture medium is exchanged to solutions that contained 0.1% DMSO or 10 μM JW55 for RKO cells and 0.1% DMSO or 10, 5, or 1 μM JW55 for SW480 cells. All samples consist of a minimum of 6 replicates. The plate is incubated in an IncuCyte inside a cell culture incubator. Images are captured every second hour to monitor proliferation[1]. |
Animal experiment: | Mice[1] Seven 12-week old female ApcCKO/CKO/Lgr5-CreERT2 mice are injected intraperitonally with 25 mg/kg of Tamoxifen diluted in an ethanol and corn oil (ratio 1:4). The mice are randomized into 2 groups and treated with either JW55 (100 mg/kg) or vehicle (DMSO). Daily per oral applications started the day after and continued for 3 weeks. The mouse body weight is measured twice a week. The mice are sacrificed and the intestines are dissected, washed in PBS, and fixed in formaldehyde [10% solution (v/v) in PBS]. The small intestines are stained using 1% methylene blue prepared in 10% paraformalaldehyde (PFA)/PBS solution. Small ileum Swiss-rolls are embedded in paraffin sectioned and stained with hematoxylin and eosin. Fixed colons are embedded in paraffin, sectioned and stained with an anti-β-catenin antibody. The number and size of the intestinal lesions are quantified by the Ellipse program. |
参考文献: [1]. Waaler J, et al. A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice. Cancer Res. 2012 Jun 1;72(11):2822-32. | |
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