XAV-939 selectively inhibits β-catenin-mediated transcription. XAV-939 stimulates β-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2 with IC50 values of 5 nM and 2 nM, respectively [1，2].
XAV-939 inhibited mouse neurofibroma sphere formation with IC50 of 0.1 μM. Western blot confirmed a 50% decrease in total β-catenin with 3 days of XAV-939 exposure (10 nM) [3]. TNKS1 plays a role in cell cycle regulation and that XAV-939 induces an accumulation of NB cell lines at G2/M and S phase of the cell cycle [4].
XAV-939 increases Irradiation (IR) sensitivity of cervical cancer with the PIK3CA-E545K mutation in vivo, XAV-939 and IR inhibited tumor weight by 38% from IR alone in that with PIK3CA-WT [5]. Combinatorial inhibition of transforming growth factor-β (TGF-β) and WNT signaling with SB431542 and XAV-939 potently enhances the efficiency, quality, and speed of reprogrammed iCMs generated upon delivery of the minimal transcription factor (TF) cocktail, GMT, into postnatal cardiac fibroblasts. SB431542 and XAV-939 significantly improved in vivo reprogramming and cardiac function in mice compared with GMT alone and reduced the number of TFs needed for human reprogramming [6].
References:
[1]. S.M. Huang, Y.M. Mishina, S. Liu, A. Cheung, F. Stegmeier, G.A. Michaud, O. Charlat, E. Wiellette, Y. Zhang, S. Wiessner, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signaling.Nature, 461 (2009), pp. 614-620
[2]. Mohit Narwal, et al. Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity. J Med Chem. 2013 Oct 24;56(20):7880-9.
[3]. Wu J, Keng VW, Patmore DM, et al. Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin pathway driving neurofibroma initiation. Cell Rep. 2016;14:1979-90.
[4]. X.H. Tian, W.J. Hou, Y. Fang, J. Fan, H. Tong, S.L. Bai, et al. XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res, 32 (1) (2013 Dec 5), p. 1
[5]. Jiang W, Wu Y, He T, et al. Targeting of beta-catenin reverses radioresistance of cervical cancer with the PIK3CA E545K mutation. Mol Cancer Ther 2020;19(2):337-47.
[6]. Mohamed, T. M. et al. Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation 135, 978-995 (2017).
XAV-939 选择性抑制 β-连环蛋白介导的转录。 XAV-939 通过稳定轴蛋白（破坏复合物的浓度限制成分）来刺激 β-连环蛋白降解。 XAV939 通过抑制多聚 ADP 核糖基化酶 tankyrase 1 和 tankyrase 2 来稳定 axin，IC50 值分别为 5 nM 和 2 nM [1，2]。
XAV-939 抑制小鼠神经纤维瘤球体形成，IC50 为 0.1 μM。 Western blot 证实，XAV-939 暴露 (10 nM) 3 天后，总 β-连环蛋白减少了 50% [3]。 TNKS1在细胞周期调控中发挥作用，XAV-939诱导NB细胞系在细胞周期的G2/M期和S期积累[4]。
XAV-939 在体内增加了具有 PIK3CA-E545K 突变的宫颈癌的辐照 (IR) 敏感性，XAV-939 和 IR 抑制了 38% 的肿瘤重量，与 PIK3CA-WT 单独使用 IR 相比 [5] 。使用 SB431542 和 XAV-939 联合抑制转化生长因子-β (TGF-β) 和 WNT 信号转导，可有效提高将最小转录因子 (TF) 混合物 GMT 递送至细胞内后生成的重编程 iCM 的效率、质量和速度产后心脏成纤维细胞。与单独使用 GMT 相比，SB431542 和 XAV-939 显着改善了小鼠的体内重编程和心脏功能，并减少了人类重编程所需的 TF 数量[6]。