Description
Tankyrases (TNKS) are poly(ADP-ribose) polymerases (PARPs) that cleave NAD
+ to produce nicotinamide and ADP-ribose, which is then covalently attached to an acceptor protein in a process known as poly(ADP-ribosyl)ation. TNKS have key roles in the Wnt signaling pathway as part of the β-catenin destruction complex. JW 74 is an inhibitor of the catalytic PARP domain of TNKS1/2 that blocks canonical Wnt signaling with an IC
50 value of 790 nM. It increases the levels of Axin2 and decreases β-catenin levels in colorectal cancer (CRC) cells, leading to down-regulation of Wnt target genes. JW 74 inhibits the growth of CRC xenograft tumors in mice. JW 74 induces apoptosis and differentiation in osteosarcoma cell lines.
Uses
JW 74 is an inhibitor that affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines.
in vitro
previous study found that jw74 at the molecular level induced stabilization of axin2, a key component of the β-catenin destruction complex, leading to reduced levels of nuclear β-catenin. in addition, jw74 could induce reduced cell growth in all tested cell lines, partially due to a delay in cell cycle progression and partially because of an induction of caspase-3-mediated apoptosis. moreover, jw74 was able to induce the differentiation in u2os cells and also enhance differentiation of os cell lines that did not harbor a differentiation block [1].
in vivo
previous animal study found that the dose of 150 mg/kg of jw74 in apcmin model could reduce the small intestinal adenoma by 48% and was comparable with celecoxib or rofecoxib. furthermore, it was noteworthy that jw74 became rapidly cleared from the blood stream due to its poor in vivo stability [2].
IC 50
790 nm for canonical wnt signaling
References
1. e. w. stratford, j. daffinrud, e. munthe, et al. the tankyrase-specific inhibitor jw74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines. cancer med. 3(1), 36-46 (2014).2. waaler j et al. novel synthetic antagonists of canonical wnt signaling inhibit colorectal cancer cell growth. cancer res. 2011 jan 1;71(1):197-205.
