生物活性

• 靶点	GSK-3β IC50:30nM

• 描述Glycogen synthase kinase 3β (GSK-3β), a component of the adenomatous polyposis coli/axin/GSK-3β complex, is involved in the ubiquitination and proteasomal degradation of β-catenin, which is the key molecule of the Wnt/β-catenin pathway ^[3]. Wnt/β-catenin pathway plays a critical role in carcinogenesis, embryonic development, i and insulin sensitivity^[4]. TWS119 is a specific inhibitor of GSK-3β, its tight binding to GSK-3 was quantified by SPR and further demonstrated by its potent GSK-3 kinase inhibitory activity (IC₅₀=30 nM) ^[5]. In vitro study revealed that treatment with TWS119 at dose 10 μM for 24 h of incubation not only significantly attenuated mRNA level of CD16 and increased the mRNA expression of CD206, but also reduced the percentage of CD16/32 positive cells and increased the percentage of CD206 positive cells in microglia cells stimulated by LPS plus IFN-γ, indicating a direct modulating effect of TWS119 on switch of microglial polarization from pro-inflammatory phenotype to antiinflammatory phenotype^[6]. Another in vitro finding showed that TWS119 at dose of 7μM enhanced IL-2 production in Tcm cells from TILs, increased IL-2-secreting CD4+ Tem cells in TILs, and promoted the proliferation of CD8+ Teff cells in TILs from human lung cancer^[7]. Furthermore, TWS119 had the ability to inhibit the activities of PC-3 cells and SW620 cells, suggesting its anticancer effect on prostate and colon cancer cells ^[8]. In an HCT116 xenograft tumor model, the tumor growth in BALB/c nude mice which received intratumoural injection with γδT cells pretreated with 2.0 μM of TWS119 was slower than the other groups, indicating its potent antitumor efficacy in vivo^[9]. TWS119 ameliorated microglia-mediated neuroinflammatory status following ischemic stroke and promoted angiogenesis by modulating microglia to anti-inflammatory phenotype^[6].
• 作用机制TWS119 binds to GSK-3β then activates the canonical Wnt-β catenin signaling pathway to result in β catenin accumulation, which leads to the expression of genes downstream of canonical Wnt signaling^[10].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  RAW 264.7	0-10000ng/ml	Cytotoxicity Assay	24 h	induces cell death in a dose dependent manner	24330853

• 动物研究
  剂量	Rat: 30 mg/kg[3] (i.p.) Mice: 20 mg/kg, 40 mg/kg[3](i.p.)
  给药途径	i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01087294	Leukemia, B-cell ... more >> Lymphoma, Hodgkins Lymphoma, Non-hodgkins Lymphoma, B-Cell Collapse <<	Phase 1	Recruiting	March 1, 2024	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting Bethesda, Maryland, United States, 20892 Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937       Contact: Referral Line NCI Experimental Transplantation and Immunology Branch    (301) 435-5942    nci-transplant@mail.nih.gov Collapse <<

• 参考文献

• [1] Muralidharan S, Hanley PJ, et al. Activation of Wnt signaling arrests effector differentiation in human peripheral and cord blood-derived T lymphocytes. J Immunol. 2011 Nov 15;187(10):5221-32.

  [2] Kordes C, Sawitza I, et al. Canonical Wnt signaling maintains the quiescent stage of hepatic stellate cells. Biochem Biophys Res Commun. 2008 Feb 29;367(1):116-23.

  [3] Wang W. GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats. Mol Neurobiol. 2016 Dec;53(10):7028-7036. doi: 10.1007/s12035-015-9607-2. Epub 2015 Dec 15.

  [4] Wnt signaling pathway

  [5] Ding S. Synthetic small molecules that control stem cell fate. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7632-7. doi: 10.1073/pnas.0732087100. Epub 2003 Jun 6.

  [6] Song D. Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke. J Neuroinflammation. 2019 Dec 6;16(1):256. doi: 10.1186/s12974-019-1660-8.

  [7] Tang YY. Effects of Glycogen Synthase Kinase-3β Inhibitor TWS119 on Proliferation and Cytokine Production of TILs From Human Lung Cancer. J Immunother. 2018 Sep;41(7):319-328. doi: 10.1097/CJI.0000000000000234.

  [8] Sun A. GSK-3β controls autophagy by modulating LKB1-AMPK pathway in prostate cancer cells. Prostate. 2016 Feb;76(2):172-83. doi: 10.1002/pros.23106. Epub 2015 Oct 6.

  [9] Chen YQ. Wnt pathway activator TWS119 enhances the proliferation and cytolytic activity of human γδT cells against colon cancer. Exp Cell Res. 2018 Jan 1;362(1):63-71. doi: 10.1016/j.yexcr.2017.11.003. Epub 2017 Nov 16.

  [10] Muralidharan S, Hanley PJ. Activation of Wnt signaling arrests effector differentiation in human peripheral and cord blood-derived T lymphocytes. J Immunol. 2011 Nov 15;187(10):5221-32. doi: 10.4049/jimmunol.1101585. Epub 2011 Oct 19.

• 更多

• Collapse