Synonym
JW55; JW-55; JW 55.
IUPAC/Chemical Name
N-(4-(((4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)furan-2-carboxamide
InChi Key
ZJZWZIXSGNFWQQ-UHFFFAOYSA-N
InChi Code
InChI=1S/C25H26N2O5/c1-30-21-10-6-19(7-11-21)25(12-15-31-16-13-25)17-26-23(28)18-4-8-20(9-5-18)27-24(29)22-3-2-14-32-22/h2-11,14H,12-13,15-17H2,1H3,(H,26,28)(H,27,29)
SMILES Code
O=C(C1=CC=CO1)NC2=CC=C(C(NCC3(C4=CC=C(OC)C=C4)CCOCC3)=O)C=C2
Appearance
white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
JW 55 is a potent and selective β-catenin signaling pathway inhibitor, which functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2).
In vitro activity:
The cell lines SW480 and HCT-15 (mutated in codon 1338 and 1417 of the APC gene, respectively) were stably transfected with ST-Luc and Renilla and incubated at various doses of JW55 for 48 hours. A dose-dependent reduction of luciferase activity was detected in both cell lines. JW55 was effective in the range of 1 to 5 μmol/L in SW480 cells and 0.01 to 5 μmol/L in HCT-15 cells (Fig. 2B, left). Next, HCT116 CRC cells with integrated ST-Luc and Renilla reporters were used to test JW55. HCT116 carries a point mutation in the CK1α-dependent phosphorylation site S45 of one β-catenin allele; however, S45-mutated β-catenin may still be phosphorylated in the remaining GSK3β phosphorylation sites (e.g. S33, S37, and T41), with resulting semiregulated β-catenin turnover. In HCT116 cells, JW55 was effective in the range of 0.01 to 5 μmol/L (Fig. 2B, right). A basal luciferase expression level at approximately 50% was reached after exposure to 5 μmol/L in the CRC cells.
Reference: Cancer Res. 2012 Jun 1;72(11):2822-32. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22440753
In vivo activity:
To evaluate the JW55-mediated decrease of intestinal tumor development in vivo, ApcCKO/CKOLgr5-CreERT2+ mice were injected intraperitoneally with a 25 mg/kg single dose of tamoxifen. A day after, daily per oral applications of JW55 (100 mg/kg; 3 females) or vehicle (DMSO; 4 females) were initiated. The dose of 100 mg/kg was chosen to counteract the rapid liver metabolism of JW55 as indicated by the human liver microsome stability analysis (t½ = 10.1 minutes; Supplementary Fig. S7A). No measurable effects on mouse body weight were noticed throughout the experiment period (Supplementary Fig. S7B). After 21 days, the mice were sacrificed and the dissected intestines were embedded in paraffin and sectioned. Immunohistochemical staining revealed that the neoplastic lesions expressed β-catenin and the mouse ISC marker Ephrin type-B receptor 2 (EphB2), indicating aberrant activation of canonical Wnt signaling in the tumor tissue (Fig. 7B; refs. 44, 48–50). The β-catenin–stained colon adenomas contrasted with the surrounding healthy mucosa, and image analysis software (Ellipse) was used to quantify the number and areas of β-catenin–positive lesions in the colon (Supplementary Fig. S7C). As it was impossible to distinguish the borders of individual tumors in the small intestine (ileum), only the total tumor area per mouse was recorded. In the ileum, a significant reduction of the total tumor area was observed after JW55 injections (mean: 2.93 mm2 and median: 2.95 mm2) when compared with the control group (mean: 8.84 mm2 and median: 9.51 mm2; normality test failed, rank sum test: P = 0.003; Fig. 7A and C, top panel). In the colon, the tumor count was substantially reduced in JW55-treated mice (mean: 9.7 and median: 6.0) when evaluated against the control group (mean: 33.8 and median: 26.0; normality test failed, rank sum test: P = 0.057; Fig. 7C, bottom panel). Furthermore, a significant decrease of the total tumor area was noticed after injections with JW55 (mean: 0.022 mm2) when compared with the control group (mean: 0.154 mm2; Students t test: P = 0.009; Fig. 7C, bottom panel). The area of single tumors was significantly reduced after injections with JW55 (mean: 0.0025 mm2) when compared with the untreated group (mean: 0.0049 mm2; Students t test: P = 0.043; Fig. 7C, bottom panel). Interestingly, the proportion of cells that expressed Ki67, a marker of proliferating and ISC-like cells, was substantially decreased in adenomas exposed to JW55 when compared with tumors that developed in the control mice (Fig. 7B, panel h and i).
Reference: Cancer Res. 2012 Jun 1;72(11):2822-32. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22440753
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
50.0 |
115.08 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
434.48
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
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 Jun 1;72(11):2822-32. doi: 10.1158/0008-5472.CAN-11-3336. Epub 2012 Mar 22. PMID: 22440753.
In vivo protocol:
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 Jun 1;72(11):2822-32. doi: 10.1158/0008-5472.CAN-11-3336. Epub 2012 Mar 22. PMID: 22440753.
1: Mao J, Hu X, Xiao Y, Yang C, Ding Y, Hou N, Wang J, Cheng H, Zhang X. Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice. Diabetes. 2013 Nov;62(11):3736-46. doi: 10.2337/db13-0035. Epub 2013 Jul 24. PubMed PMID: 23884889; PubMed Central PMCID: PMC3806619.
2: 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 Jun 1;72(11):2822-32. doi: 10.1158/0008-5472.CAN-11-3336. Epub 2012 Mar 22. PubMed PMID: 22440753.
