XAV-939的生物活性
XAV939 is a small molecule and selective Wnt pathway β-catenin-mediated transcription inhibitor and axin stabilizing agent with IC50 of 11 and 4 nM for the inhibition of TNKS1 and TNKS2, respectively.
IC50 Value: 11 nM(TNKS1); 4 nM(TNKS2)
Target: TMKS1/2; β-catenin
in vitro: XAV-939 specifically inhibits tankyrase PARP activity. XAV-939 dramatically decreases DNA-PKcs protein levels, confirming the critical role of tankyrase poly-ADP-ribosylation activity in maintaining stability of the DNA-PKcs protein. The greatest reduction of DNA-PKcs protein levels (< 25% relative expression compared to DMSO treated controls) occurs at 12 hours with 1.0 μM XAV-939 exposure. Treatment of human lymphoblasts with 1.0 μM XAV-939 results in marked elevation of tankyrase 1 levels. XAV-939 is axin stabilizing agent. XAV-939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. XAV-939 stabilizes axin by blocking the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. XAV-939 deregulates the Wnt/b-catenin pathway which has been implicated in many cancers.
in vivo: N/A
相关文献
[1]. Huang SM et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009 Oct 1;461(7264):614-20.
[2]. Li Z, Yamauchi Y, Kamakura M, Murayama T, Goshima F, Kimura H, Nishiyama Y. ,Herpes simplex virus requires poly(ADP-ribose) polymerase activity for efficient replication and induces extracellular signal-related kinase-dependent phosphorylation and ICP0-dependent nuclear localization of tankyrase 1. J Virol. 2012 Jan;86(1):492-503. Epub 2011 Oct 19.
[3]. Kirby CA, Cheung A, Fazal A, Shultz MD, Stams T.,Structure of human tankyrase 1 in complex with small-molecule inhibitors PJ34 and XAV939.,Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Feb 1;68(Pt 2):115-8. Epub 2012 Jan 21.
[4]. Ao A, Hao J, Hopkins CR, Hong CC.,DMH1, a Novel BMP Small Molecule Inhibitor, Increases Cardiomyocyte Progenitors and Promotes Cardiac Differentiation in Mouse Embryonic Stem Cells.,PLoS One. 2012;7(7):e41627. Epub 2012 Jul 27. bryonic Stem Cells. ,PLoS One. 2012;7(7):e41627. Epub 2012 Jul 27.
[5]. Chen HC, Zhu YT, Chen SY, Tseng SC.,Wnt signaling induces epithelial-mesenchymal transition with proliferation in ARPE-19 cells upon loss of contact inhibition.,Lab Invest. 2012 May;92(5):676-87.