NVP-TNKS656 is an orally bioavailable inhibitor of tankyrase 2 (TNKS2; IC50 = 6 nM). It is selective for TNKS2 over poly(ADP-ribose) polymerase (PARP) 1 and 2 (IC50s = >19 and 32 nM, respectively). NVP-TNKS656 inhibits Wnt ligand-induced signaling with an IC50 value of 3.5 nM in an HEK293 cell reporter assay. In vivo, NVP-TNKS656 (350 mg/kg) reduces Axin 2 mRNA expression, a Wnt/β-catenin target gene, in MMTV-Wnt1 tumor bearing mice.
the ic50 value of nvp-tnks656 against parp1, tnks2, parp2, and stf was > 19, 0.006, 32, and 0.0035 μm, respectively [1].
the clearance and volume of distribution of nvp-tnks656 were 10 ml/min/kg and 0.6 l/kg after intravenous administration in mice. the exposure and oral bioavailability was 32% and 53%, respectively. in the mouse mammary tumor virus (mmtv)-wnt1 transgenic model, oral administration of nvp-tnks656 (350 mg/kg) activated the wnt signaling over a 24-h time course. nvp-tnks656 treatment reduced the wnt/beta-catenintarget gene axin2 mrna level by 70-80% [1].
shultz m d, cheung a k, kirby c a, et al. identification of nvp-tnks656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor[j]. journal of medicinal chemistry, 2013, 56(16): 6495-6511.
