JW74

JW74 is a tankyrase-specific inhibitor. JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines. At the molecular level, JW74 induces stabilization of AXIN2, a key component of the β-catenin destruction complex, resulting in reduced levels of nuclear β-catenin. At the functional level, JW74 induces reduced cell growth in all three tested cell lines, in part due to a delay in cell cycle progression and in part due to an induction of caspase-3-mediated apoptosis. Furthermore, JW74 induces differentiation in U2OS cells, which under standard conditions are resistant to osteogenic differentiation. JW74 also enhances differentiation of OS cell lines, which do not harbor a differentiation block. ( Cancer Med. 2014 Feb;3(1):36-46. )

Product information

CAS Number: 863405-60-1

Molecular Weight: 456.52

Formula: C24H20N6O2S

Chemical Name: 5-(((4-(4-methoxyphenyl)-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-3-(p-tolyl)-1,2,4-oxadiazole

Smiles: CC1C=CC(=CC=1)C1N=C(CSC2=NN=C(C3C=CN=CC=3)N2C2C=CC(=CC=2)OC)ON=1

InChiKey: KRIKILRRJCIWNB-UHFFFAOYSA-N

InChi: InChI=1S/C24H20N6O2S/c1-16-3-5-17(6-4-16)22-26-21(32-29-22)15-33-24-28-27-23(18-11-13-25-14-12-18)30(24)19-7-9-20(31-2)10-8-19/h3-14H,15H2,1-2H3

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

JW74 shows a reduction of canonical Wnt signaling in the ST-Luc assay with an IC50 of 790 nM. The effect of tankyrase inhibition on cellular viability is tested by performing an MTS assay. The cellular viability of U2OS cells treated for 72 h treatment with 10 μM JW74 is reduced to 80%, relative to DMSO-treated cells. Flow cytometry is also performed to determine the expression marker Ki-67 in U2OS following 48 h treatment with DMSO or 10 uM JW74. Ki-67 expression is reduced from 97.5% in DMSO-treated cells to 86.7% in JW74-treated cells.

In Vivo:

The in vivo efficacy of JW74 is tested using SW480 cell xenografts. A relatively high dose of JW74 (150 or 300 mg/kg) is used because of a rapid compound degradation in the organism as indicated in the human liver microsome analysis (t1/2=2.5 minutes) and in pharmacokinetic analyses (after per oral injections: t1/2=30 minutes and intravenous injections: t1/2=15 minutes). The presence of JW74 in tumors and plasma is identified by mass spectrometry. JW74 concentration in tumors is in the range 4.2 to 72.1 μmol/kg for JW74 150 mg/kg, 1.9 to 11.1 μmol/kg for JW74 300 mg/kg, and 2.8 μM in plasma for both doses.

References:

1. Liu D, Cui W, Liu B, Hu H, Liu J, Xie R, Yang X, Gu G, Zhang J, Zheng H. Atorvastatin Protects Vascular Smooth Muscle Cells From TGF-β1-Stimulated Calcification by Inducing Autophagy via Suppression of the β-Catenin Pathway. Cell Physiol Biochem. 2014;33(1):129-41. doi: 10.1159/000356656. Epub 2014 Jan 20. PubMed PMID: 24481040.
2. Wessel Stratford E, Daffinrud J, Munthe E, Castro R, Waaler J, Krauss S, Myklebost O. The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines. Cancer Med. 2014 Feb;3(1):36-46. doi: 10.1002/cam4.170. Epub 2013 Dec 17. PubMed PMID: 24403055; PubMed Central PMCID: PMC3930388.
3. Voronkov A, Holsworth DD, Waaler J, Wilson SR, Ekblad B, Perdreau-Dahl H, Dinh H, Drewes G, Hopf C, Morth JP, Krauss S. Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor. J Med Chem. 2013 Apr 11;56(7):3012-23. doi: 10.1021/jm4000566. Epub 2013 Mar 29. PubMed PMID: 23473363.
4. Waaler J, Machon O, von Kries JP, Wilson SR, Lundenes E, Wedlich D, Gradl D, Paulsen JE, Machonova O, Dembinski JL, Dinh H, Krauss S. Novel synthetic antagonists of canonical Wnt signaling inhibit colorectal cancer cell growth. Cancer Res. 2011 Jan 1;71(1):197-205. doi: 10.1158/0008-5472.CAN-10-1282. PubMed PMID: 21199802.

Products are for research use only. Not for human use.