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].

• 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.