产品号 #73512_C
WNT通路激活剂；抑制GSK3β
总览
TWS119是一种强效的二取代吡咯嘧啶类糖原合酶激酶3β（GSK3β）抑制剂，IC₅₀值为30 nM，Kd为126 nM（Ding et al.）。GSK3是一种丝氨酸/苏氨酸激酶，是WNT通路的关键抑制剂；因此，TWS119可作为WNT通路的激活剂。
维持培养
·维持Wistar大鼠肝星状细胞的双效静息状态（Kordes et al.）。
分化
·诱导小鼠胚胎癌和胚胎干细胞向神经元分化（Ding et al.）。
·诱导小鼠或人CD8+ T细胞产生T记忆干细胞样（T-SCM）细胞，并有证据表明，在小鼠来源的T-SCM过继转移后，T-SCM的持久性、增殖和抗肿瘤活性均有所增强（Forget et al.; Gattinoni et al.）。
癌症研究
·抑制人肺泡横纹肌肉瘤细胞增殖并诱导其凋亡（Zeng et al.）。
细胞类型
癌细胞及细胞系，多能干细胞，T 细胞
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
应用
分化，培养
研究领域
癌症，免疫，干细胞生物学
CAS 编号
601514-19-6
化学式
C₁₈H₁₄N₄O₂
纯度
≥ 90%
通路
WNT
靶点
GSK3β
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Applications
This product is designed for use in the following research area(s) as part of the highlighted workflow stage(s). Explore these workflows to learn more about the other products we offer to support each research area.
Resources and Publications
Educational Materials (3)
Publications (5)
Stimulation of Wnt/ß-catenin pathway in human CD8+ T lymphocytes from blood and lung tumors leads to a shared young/memory phenotype. PloS one 2012
Abstract
Cancer can be treated by adoptive cell transfer (ACT) of T lymphocytes. However, how to optimally raise human T cells to a differentiation state allowing the best persistence in ACT is a challenge. It is possible to differentiate mouse CD8(+) T cells towards stem cell-like memory (T(SCM)) phenotype upon TCR stimulation with Wnt/ß-catenin pathway activation. Here, we evaluated if T(SCM) can be obtained from human mature CD8(+) T cells following TCR and Wnt/ß-catenin activation through treatment with the chemical agent 4,6-disubstituted pyrrolopyrimidine (TWS119), which inhibits the glycogen synthase kinase-3β (GSK-3β), key inhibitor of the Wnt pathway. Human CD8(+) T cells isolated from peripheral blood or tumor-infiltrating lymphocytes (TIL), and treated with TWS119 gave rise to CD62L(+)CD45RA(+) cells, indicative of early differentiated stage, also expressing CD127 which is normally found on memory cells, and CD133, an hematopoietic stem cell marker. T(SCM) cells raised from either TIL or blood secreted numerous inflammatory mediators, but in lower amounts than those measured without TWS119. Finally, generated T(SCM) CD8(+) T cells expressed elevated Bcl-2 and no detectable caspase-3 activity, suggesting increased persistence. Our data support a role for Wnt/ß-catenin pathway in promoting the T(SCM) subset in human CD8(+) T cells from TIL and the periphery, which are relevant for ACT.
Glycogen synthase kinase 3 regulates PAX3-FKHR-mediated cell proliferation in human alveolar rhabdomyosarcoma cells. Biochemical and biophysical research communications 2010
Abstract
Patients with alveolar rhabdomyosarcoma (ARMS) have poorer response to conventional chemotherapy and lower survival rates than those with embryonal RMS (ERMS). To identify compounds that preferentially block the growth of ARMS, we conducted a small-scale screen of 160 kinase inhibitors against the ARMS cell line Rh30 and ERMS cell line RD and identified inhibitors of glycogen synthase kinase 3 (GSK3), including TWS119 as ARMS-selective inhibitors. GSK3 inhibitors inhibited cell proliferation and induced apoptosis more effectively in Rh30 than RD cells. Ectopic expression of fusion protein PAX3-FKHR in RD cells significantly increased their sensitivity to TWS119. Down-regulation of GSK3 by GSK3 inhibitors or siRNA significantly reduced the transcriptional activity of PAX3-FKHR. These results suggest that GSK3 is directly involved in regulating the transcriptional activity of PAX3-FKHR. Also, GSK3 phosphorylated PAX3-FKHR in vitro, suggesting that GSK3 might regulate PAX3-FKHR activity via phosphorylation. These findings support a novel mechanism of PAX3-FKHR regulation by GSK3 and provide a novel strategy to develop GSK inhibitors as anti-ARMS therapies.
Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature medicine 2009
Abstract
Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt-beta-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt-beta-catenin signaling by inhibitors of glycogen sythase kinase-3beta or the Wnt protein family member Wnt3a arrested CD8(+) T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44(low)CD62L(high)Sca-1(high)CD122(high)Bcl-2(high) self-renewing multipotent CD8(+) memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8(+) T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 601514-19-6 |
| Chemical Formula | C₁₈H₁₄N₄O₂ |
| Purity | ≥ 90% |
| Target | GSK3β |
| Pathway | WNT |
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