3D-QSAR analysis of benzimidazole inhibitors of interleukin-2 inducible T cell kinase (ITK) considering receptor flexibility and water importance for molecular alignment

2013 ◽  
Vol 22 (11) ◽  
pp. 5578-5587 ◽  
Author(s):  
Malkeet Singh Bahia ◽  
Om Silakari
Keyword(s):  
T Cell ◽  
Interleukin 2 ◽  
3D Qsar ◽  
Molecular Alignment ◽  
Qsar Analysis ◽  
Receptor Flexibility ◽  
Inducible T Cell Kinase

scholarly journals Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT

2020 ◽  
Vol 11 ◽  
Author(s):  
Mahinbanu Mammadli ◽  
Weishan Huang ◽  
Rebecca Harris ◽  
Aisha Sultana ◽  
Ying Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Treatment Strategies ◽  
Receptor Expression ◽  
Hematopoietic Stem ◽  
Target Organs ◽  
Donor T Cells ◽  
Inducible T Cell Kinase

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood Assay

2012 ◽  
Vol 55 (22) ◽  
pp. 10047-10063 ◽  
Author(s):  
Christoph W. Zapf ◽  
Brian S. Gerstenberger ◽  
Li Xing ◽  
David C. Limburg ◽  
David R. Anderson ◽  
...  
Keyword(s):  
T Cell ◽  
Whole Blood ◽  
Interleukin 2 ◽  
Whole Blood Assay ◽  
Blood Assay ◽  
Covalent Inhibitors ◽  
Inducible T Cell Kinase

scholarly journals Magnesium Restores Activity to Peripheral Blood Cells in a Patient With Functionally Impaired Interleukin-2-Inducible T Cell Kinase

2019 ◽  
Vol 10 ◽  
Author(s):  
Matthew K. Howe ◽  
Kennichi Dowdell ◽  
Amitava Roy ◽  
Julie E. Niemela ◽  
Wyndham Wilson ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Interleukin 2 ◽  
Peripheral Blood Cells ◽  
Functionally Impaired ◽  
Inducible T Cell Kinase

scholarly journals Interleukin-2–inducible T-cell kinase inhibitors modify functional polarization of human peripheral T-cell lymphoma cells

2019 ◽  
Vol 3 (5) ◽  
pp. 705-710
Author(s):  
Sami Mamand ◽  
Matthew Carr ◽  
Rebecca L. Allchin ◽  
Matthew J. Ahearne ◽  
Simon D. Wagner
Keyword(s):  
T Cell ◽  
Kinase Inhibitors ◽  
Interleukin 2 ◽  
Culture Conditions ◽  
Human Tonsil ◽  
Functional Changes ◽  
Key Points ◽  
Normal Human ◽  
Functional Polarization ◽  
Inducible T Cell Kinase

Key Points ITK inhibitors perturb functional changes due to polarizing culture conditions in normal human tonsil CD4+ T cells. Primary human PTCL cells alter their functional properties in culture and ITK inhibitors modify these changes.

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