Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck

Calderwood, David J.; Johnston, David N.; Munschauer, Rainer; Rafferty, Paul

doi:10.1016/s0960-894x(02)00195-6

Cited by 54 publications

(39 citation statements)

References 11 publications

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“…When used at 1 mmol/L, we found that this compound effectively inhibits LCK without affecting Lyn. This finding concurs with those of other studies reporting the specificity of Lck-i (33)(34)(35), and is important because Lyn is constitutively active in CLL cells (13). Thus, treatment of CLL cells with 1 mmol/L Lck-i significantly reduces BCR-induced activation of the NF-kB, ERK, and PI3K/Akt signaling pathways.…”

Section: Discussionsupporting

confidence: 91%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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B-cell receptor (BCR) signals promote survival of chronic lymphocytic leukemia (CLL) cells, and it is believed that overexpressed and constitutively active Lyn mediates this signaling. Here, we show that CLL cells express lymphocyte-specific protein tyrosine kinase (LCK) and that inhibition of this Src family tyrosine kinase with the specific inhibitor [4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane (Lck-i)], or reduction of its expression with siRNA, blocks the induction of CD79a, Syk, inhibitor of IkB kinase (IKK), Akt, and extracellular signal-regulated kinase (ERK) phosphorylation by BCR cross-linking in these cells. Furthermore, we show that CLL cells with high levels of LCK expression have higher levels of BCR-mediated IKK, Akt, and ERK phosphorylation as well as cell survival than CLL cells with low levels of LCK expression. We also show that treatment of CLL cells with Lck-i inhibits BCR cross-linking-induced cell survival. Taken together, these data show a major role for LCK in proximal and distal BCR-mediated signaling in CLL cells and suggest that LCK expression is important in the pathogenesis of this disease. On a clinical level, these studies advocate the use of specific LCK inhibitors in the treatment of progressive CLL. Mol Cancer Res; 11(5); 541-54. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 91%

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

Talab

Allen

Thompson

et al. 2013

Molecular Cancer Research

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“…To test this possibility, cells from animals that were d2 or d6 postinfection were treated with titrated concentrations of the Src kinase inhibitor, 7C-PP (cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo [2,3-d]pryrimidin-4-ylamine) (8,11,14). Increased susceptibility to these inhibitors has been previously reported to correlate with low functional avidity (51).…”

Section: High Avidity Cells Present At Early Times Can Give Rise To Lmentioning

confidence: 99%

In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection

et al. 2013

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Numerous studies have demonstrated a critical role for T cell avidity in predicting in vivo efficacy. Even though the measurement of avidity is now a routine assessment for the analysis of effector and memory T cell populations, our understanding of how this property is controlled in vivo at both the population and individual cell levels is limited. Our previous studies have identified high avidity as a property of the initial effector population generated in mice following respiratory virus infection. As the response progresses, lower avidity cells appear in the effector pool. The studies described here investigate the mechanistic basis of this in vivo regulation of avidity. We present data supporting in vivo avidity modulation within the early high avidity responders that results in a population of lower avidity effector cells. Changes in avidity were correlated with decreased lck expression and increased sensitivity to lck inhibitors in effector cells present at late versus early times postinfection. The possibility of tuning within select individual effectors is a previously unappreciated mechanism for the control of avidity in vivo.

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“…To implicate Src family kinases in the phosphorylation of the Bcr-Abl SH3 domain in CML cells, we employed the Src family kinase inhibitor A-419259 (31). Previous studies by our group have shown that this compound blocks Src family kinase activity in vitro in the low nanomolar range, but is at least 2 orders of magnitude less active against the Abl kinase domain (18,26).…”

mentioning

confidence: 99%

Src Family Kinases Phosphorylate the Bcr-Abl SH3-SH2 Region and Modulate Bcr-Abl Transforming Activity

Meyn

Wilson

Abdi³

et al. 2006

Journal of Biological Chemistry

113

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Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck

Cited by 54 publications

References 11 publications

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection

Src Family Kinases Phosphorylate the Bcr-Abl SH3-SH2 Region and Modulate Bcr-Abl Transforming Activity

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Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck

Cited by 54 publications

References 11 publications

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

LCK Is an Important Mediator of B-Cell Receptor Signaling in Chronic Lymphocytic Leukemia Cells

In vivoModulation of Avidity in Highly Sensitive CD8+Effector T Cells Following Viral Infection

Src Family Kinases Phosphorylate the Bcr-Abl SH3-SH2 Region and Modulate Bcr-Abl Transforming Activity

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In vivoModulation of Avidity in Highly Sensitive CD8⁺Effector T Cells Following Viral Infection