TWS119 is a potent disubstituted pyrrolopyrimidine inhibitor of glycogen synthase kinase 3 beta (GSK3β) with an IC₅₀ of 30 nM and Kd of 126 nM (Ding et al.). GSK3 is a serine/threonine kinase that is a key inhibitor of the WNT pathway; therefore TWS119 functions as a WNT pathway activator.
MAINTENANCE
· Maintains the bi-potent, quiescent state in hepatic stellate cells of Wistar rats (Kordes et al.).
DIFFERENTIATION
· Induces differentiation of mouse embryonal carcinoma and embryonic stem cells to neurons (Ding et al.).
· Induces production of T memory stem cell-like (T-SCM) cells from mouse or human CD8+ T cells with evidence of increased persistence, proliferation, and anti-tumor activity after adoptive transfer of mouse-derived T-SCM (Forget et al.; Gattinoni et al.).
CANCER RESEARCH
· Inhibits cell proliferation and induces apoptosis in human alveolar rhabdomyosarcoma cells (Zeng et al.).
MAINTENANCE
· Maintains the bi-potent, quiescent state in hepatic stellate cells of Wistar rats (Kordes et al.).
DIFFERENTIATION
· Induces differentiation of mouse embryonal carcinoma and embryonic stem cells to neurons (Ding et al.).
· Induces production of T memory stem cell-like (T-SCM) cells from mouse or human CD8+ T cells with evidence of increased persistence, proliferation, and anti-tumor activity after adoptive transfer of mouse-derived T-SCM (Forget et al.; Gattinoni et al.).
CANCER RESEARCH
· Inhibits cell proliferation and induces apoptosis in human alveolar rhabdomyosarcoma cells (Zeng et al.).
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Protocols and Documentation
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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.
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