NVP-TNKS656 is a highly potent, selective, and orally active TNKS2 inhibitor with IC50 of 6 nM, showing > 300 fold selectivity against PARP1 and PARP2.
Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. NVP-TNKS656 is a novel and selective tankyrase 2 inhibitor with IC50 value of 6nM, while exhibits inhibitory effect on PARP 1 and 2 with IC50 values up to >19μM and 32μM, respectively. NVP-TNKS656 exhibited a good PK/PD relationship as a corresponding 70−80% reduction in the Wnt/beta-catenin target gene Axin2 mRNA level, compared to vehicle control animals, could be observed in MMTV-Wnt1 tumor bearing athymic nude mice after a single oral dose of NVP-TNKS656 at 350 mg/kg over a 24-h time. Inhibition of Tankyrases through NVP-TNKS656 could potentiate MEK inhibitor activity by releasing a FGFR2 signaling feedback loop, as well as synergize with MEK inhibitor to downregulate FGFR2 signaling and enhance antitumor activity in vivo. Intraperitoneal injection with 100mg/kg twice daily blocked the Wnt/β-catenin signaling in colorectal cancer PDX models shown by reduction of nuclear β-catenin and increase of AXIN1 protein levels.
NVP-TNKS656 动物研究
Animal study
NVP-TNKS656 (30 or 100 mg/kg, orally administered) demonstrates favorable exposure and moderate oral bioavailability of 32% and 53%, respectively. A slight overproportional increase in oral exposure is observed between 30 and 100 mg/kg, with the dose-normalized AUC for the 100 mg/kg dose being 2-fold higher than for the 30 mg/kg dose. Mice treated with NVP-TNKS656 (350 mg/kg, orally administered) exhibit good plasma and tumor exposures corresponding to AUC0-24h of 515 and 325 μM·h, respectively [1].
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