XAV-939 

XAV-939 是有效的 tankyrase 抑制劑，靶向 Wnt/β-catenin 途徑。XAV-939 通過(guò) tankyrase 1 和 tankyrase 2 (IC50 分別為 5 和 2 nM) 來(lái)穩(wěn)定 axin，從而刺激 β-catenin 降解。XAV939 與 TNKS1 和 TNKS2 的催化 (PARP) 域緊密結(jié)合 (Kd 分別為 99 和 93 nM)。

生物活性

XAV-939 is a potent tankyrase inhibitor that targets Wnt/β-catenin signaling. XAV-939 stabilizes axin by inhibiting tankyrase 1 and tankyrase 2 (IC50s of 5 and 2 nM, respectively), thereby stimulating β-catenin degradation. XAV939 binds tightly to the catalytic (PARP) domains of TNKS1 and TNKS2 (Kds of 99 and 93 nM, respectively)[1]

體外研究(In Vitro)

XAV939 also binds to recombinant PARP1, although with a significantly lower binding affinity (Kd=1.2 μM). XAV939 (1 μM) strongly inhibis STF activity in SW480 cells, Wnt3a-stimulated STF activity in HEK293 cells, but does not affect CRE, NF-κB or TGF-β luciferase reporters. XAV939 regulates axin levels through tankyrase inhibition in HEK293 cell[1]. XAV939 (0.5 μM, 1.0 μM) reduces DNA-PKcs protein levels 50% of the relative DMSO control in human lymphoblasts[2]. XAV939 induces a second wave of pro-cardiomyocyte gene expression as shown by increased Mesp1 and Isl1expression 2 to 4 days after Wnt inhibition, and by increased Nkx2.5 expression 4 to 6 days after XAV939 addition[3]. XAV-939 (10 nM) has a suppressive effect on elevated MMP-13 levels in both IL-1β-induced SW 1353 cells[4].

體內(nèi)研究(In Vivo)

XAV-939 (3 mL, 10 nM) has a suppressive effect on elevated MMP-13 levels in the rat OA model[4]. XAV-939 (1 mg/mL, i.p.) ameliorates the psoriasiform skin disease induced by IMQ. XAV-939 results in a significant decrease in the IMQ-induced epidermal hyperplasia (indicated by acanthosis) and dermal inflammatory infiltrates in mice[5].

分子量：312.31

Formula：C14H11F3N2OS

CAS 號(hào)：284028-89-3

運(yùn)輸條件：Room temperature in continental US; may vary elsewhere.

儲(chǔ)存方式

Powder-20°C3 years

4°C2 years

In solvent-80°C6 months

-20°C1 month

溶解性數(shù)據(jù)

DMSO : 25 mg/mL (80.05 mM; ultrasonic and warming and heat to 60°C)

H2O : < 0.1 mg/mL (insoluble)

配制儲(chǔ)備液

1 mM3.2019 mL16.0097 mL32.0195 mL

5 mM0.6404 mL3.2019 mL6.4039 mL

10 mM0.3202 mL1.6010 mL3.2019 mL

*

請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；一旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。

儲(chǔ)備液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?6 個(gè)月內(nèi)使用，-20°C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?1 個(gè)月內(nèi)使用。

In Vivo:

以下溶解方案都請(qǐng)先按照 In Vitro 方式配制澄清的儲(chǔ)備液，再依次添加助溶劑：

——為保證實(shí)驗(yàn)結(jié)果的可靠性，澄清的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的工作液，建議您現(xiàn)用現(xiàn)配，當(dāng)天使用； 以下溶劑前顯示的百

分比是指該溶劑在您配制終溶液中的體積占比；如在配制過(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的方式助溶

1.請(qǐng)依序添加每種溶劑： 10% DMSO    40% PEG300    5% Tween-80    45% saline

Solubility: 2 mg/mL (6.40 mM); Suspended solution; Need ultrasonic

2.請(qǐng)依序添加每種溶劑： 10% DMSO    90% (20% SBE-β-CD in saline)

Solubility: 2 mg/mL (6.40 mM); Suspended solution; Need ultrasonic

3.請(qǐng)依序添加每種溶劑： 10% DMSO    90% corn oil

Solubility: ≥ 1.04 mg/mL (3.33 mM); Clear solution

參考文獻(xiàn)

[1]. Huang SM, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009 Oct 1;461(7264):614-620.

[2]. Dregalla RC, et al. Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs. Aging (Albany NY). 2010 Oct;2(10):691-708.

[3]. Ao A, et al. 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.

[4]. Zeng L, et al. Chondroprotective effects and multi-target mechanisms of Icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model. Int Immunopharmacol. 2014 Jan;18(1):175-81.

[5]. Bai J, et al. Epigenetic downregulation of SFRP4 contributes to epidermal hyperplasia in psoriasis. J Immunol. 2015 May 1;194(9):4185-98. doi: 10.4049/jimmunol.1403196. Epub 2015 Mar 30.

[6]. Narwal M, et al. Discovery of tankyrase inhibiting flavones with increased potency and isoenzyme selectivity. J Med Chem. 2013 Oct 24;56(20):7880-9.

[7]. Liu D, et al. Wnt/β-catenin signaling participates in the regulation of lipogenesis in the liver of juvenile turbot (Scophthalmus maximus L.). Comp Biochem Physiol B Biochem Mol Biol. 2016 Jan;191:155-62.

注：產(chǎn)品僅用于科研