XAV939 通过抑制 tankyRase1/2 显示对 Wnt/β-CATenin 介导的转录的选择性抑制。它与 TNKS1 和 TNKS2 的催化 (PARP) 域紧密结合，Kd分别为 99 和 93 nM

XAV-939 shows the selective inhibition against Wnt/β-catenin-mediated transcription by tankyrase1/2 inhibition (IC50: 11/4 nM in cell-free assays).

Examination of various treatment times (2, 5, 8, 12, 18, 24 and 48 hr) and XAV939 concentrations (0.1, 0.5 or 1.0 μM) revealed a significant reduction of DNA-PKcs protein levels by 8 hours with exposures of either 0.5 μM or 1.0 μM XAV939 [1]. XAV939 blocks TNKS binding at 0.1 μM and blocks PARP1/2 binding at 1 μM. XAV939 binds tightly to the catalytic (PARP) domains of TNKS1 and TNKS2 (Kd = 0.099 and 0.093 μM, respectively) [2].

In contrast to vehicle control (VC), administration of XAV-939 resulted in a significant decrease in the IMQ-induced epidermal hyperplasia (indicated by acanthosis) and dermal inflammatory infiltrates in mice. XAV-939 administration remarkably decreased the infiltration of F4/80+ macrophages and CD3+ T cells in inflamed skin lesions induced by IMQ. Furthermore, reduced neutrophilic infiltrates in microabscesses were observed in the lesional skin treated with XAV-939 compared with VC [3].

XAV939, the recently identified small molecule shown to specifically inhibit PARP activity of tankyrase 1 (and tankyrase 2 at higher concentrations), was used here at much lower concentrations than 3-AB. The tankyrase specific inhibitor XAV939 was solubilized in DMSO at 55°C to a stock concentration of 10mM, which was diluted to a working concentration of 100μM; final concentrations of 0.5μM or 1μM were well within the concentration parameters suggested for cell culture experiments to inhibit tankyrase specifically. Cultures were maintained under these conditions for the duration of the designated time course. Controls were exposed to DMSO alone. Following treatment, cells were lysed and prepared for western blot analysis. Tankyrase 1 and DNA-PKcs protein levels were normalized to the β-actin loading controls and quantified [1].

XAV-939, a selective inhibitor of tankyrase (TNKS)-1 and TNKS-2, was injected i.p., at a dose of 1 mg/ml, once a day for seven consecutive days of IMQ treatment (injection volume 100 μl). Control mice were injected with 100 μl 10% DMSO/90% 0.9% NaCl, the solvent for XAV-939 [3].

284028-89-3

C14H11F3N2OS

312.31

NVP-XAV939;XAV939

DMSO:6.3 mg/mL (20 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years