GW806742X

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Chemical Structure| 579515-63-2 同义名 : -
CAS号 : 579515-63-2
货号 : A1176842
分子式 : C25H22F3N7O4S
纯度 : 99%+
分子量 : 573.547
MDL号 : MFCD29036385
存储条件：

Pure form Keep in dark place,Inert atmosphere,Room temperature

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(183.07 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • MLKL

    MLKL, Kd:9.3 μM
描述 Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. RIPK3-mediated phosphorylation is thought to initiate MLKL oligomerization, membrane translocation and membrane disruption[3]. MLKL promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo[4]. MLKL-induced membrane depolarization and cell death exhibit a positive correlation to its channel activity. The Mg(2+)-preferred permeability and five transmembrane segment topology distinguish MLKL from previously identified Mg(2+)-permeable channels and thus establish MLKL as a novel class of cation channels[5].Mice deficient in MLKL (Mlkl-/-) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT[6]. MLKL activation is sufficient to induce the processing and release of bioactive IL-1β. MLKL activation triggers potassium efflux and assembly of the NLRP3 inflammasome, which is required for the processing and activity of IL-1β released during necroptosis. Notably, MLKL activation also causes cell membrane disruption, which allows efficient release of IL-1β independently of the recently described pyroptotic effector gasdermin-D[7]. GW806742X, an ATP mimetic and a potent MLKL inhibitor, binds the MLKL pseudokinase domain with a Kd of 9.3 μM. GW806742X has activity against VEGFR2 (IC50=2 nM). GW806742X retards MLKL membrane translocation and inhibits necroptosis[8].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.74mL

0.35mL

0.17mL

8.72mL

1.74mL

0.87mL

17.44mL

3.49mL

1.74mL
参考文献

[1]Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, Pierotti C, Garnier JM, Dobson RC, Webb AI, Tripaydonis A, Babon JJ, Mulcair MD, Scanlon MJ, Alexander WS, Wilks AF, Czabotar PE, Lessene G, Murphy JM, Silke J. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7. doi: 10.1073/pnas.1408987111. Epub 2014 Oct 6. PMID: 25288762; PMCID: PMC4210347.

[2]Sammond DM, Nailor KE, Veal JM, Nolte RT, Wang L, Knick VB, Rudolph SK, Truesdale AT, Nartey EN, Stafford JA, Kumar R, Cheung M. Discovery of a novel and potent series of dianilinopyrimidineurea and urea isostere inhibitors of VEGFR2 tyrosine kinase. Bioorg Med Chem Lett. 2005 Aug 1;15(15):3519-23. doi: 10.1016/j.bmcl.2005.05.096. PMID: 15990302.

[3] Andre L Samson,et al. MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis. Nat Commun. 2020 Jun 19;11(1):3151.

[4]Jialin Dai,et al. A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression. Cell Death Dis. 2020 Apr 24;11(4):282.

[5] Bingqing Xia,et al. MLKL forms cation channels. Cell Res. 2016 May;26(5):517-28.

[6]Sevda Lule,et al. Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab. 2021 Jul;41(7):1623-1633.

[7]Kimberley D Gutierrez,et al. MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D. J Immunol. 2017 Mar 1;198(5):2156-2164.

[8] Hildebrand JM, et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7.