Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design

Cook, Brian N.; Bentzien, Jörg; White, André; Nemoto, Peter A.; Wang, Ji; Man, Chuk C.; Soleymanzadeh, Fariba; Khine, Hnin Hnin; Kashem, Mohammed A.; Kugler, Stanley; Wolak, John P.; Roth, Gregory P.; Lombaert, Stéphane De; Pullen, Steven S.; Takahashi, Hidenori

doi:10.1016/j.bmcl.2008.12.028

Cited by 30 publications

(20 citation statements)

References 21 publications

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“…In vitro studies using human whole blood assays indicate that these compounds are capable of inhibiting IL-2 secretion with an IC 50 of 240 nM or 690 nM. Further in vivo studies in Balb/c mice showed that oral administration of these compounds inhibited IL-2 and IL-4 production in response to anti-CD3 antibody in a dose dependent manner with high potency [128, 129]. It should be noted that this anti-CD3 in vivo assay largely targets i NKT cells, and confirm the role of ITK in regulating the cytokine secretion of i NKT cells.…”

Section: Current Itk Inhibitorsmentioning

confidence: 99%

ITK Inhibitors in Inflammation and Immune-Mediated Disorders

Sahu

August²

2009

CTMC

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Interleukin-2-inducible T cell kinase (ITK) is a non-receptor tyrosine kinase expressed in T cells, NKT cells and mast cells which plays a crucial role in regulating the T cell receptor (TCR), CD28, CD2, chemokine receptor CXCR4 and FcεR mediated signaling pathways. In T cells, ITK is an important mediator for actin reorganization, activation of PLCγ, mobilization of calcium, and activation of the NFAT transcription factor. ITK plays an important role in the secretion of IL-2, but more critically, also has a pivotal role in the secretion of Th2 cytokines, IL-4, IL-5 and IL-13. As such, ITK has been shown to regulate the development of effective Th2 response during allergic asthma as well as infections against parasitic worms. This ability of ITK to regulate Th2 responses, along with it's pattern of expression, has led to the proposal that it would represent an excellent target for Th2 mediated inflammation. We discuss here the possibilities and pitfalls of targeting ITK for inflammatory disorders.

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Section: Current Itk Inhibitorsmentioning

confidence: 99%

ITK Inhibitors in Inflammation and Immune-Mediated Disorders

Sahu

August²

2009

CTMC

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“…The structure of the inhibitor bound to Itk has been solved and this showed that the aminobenzimidazole core is bound to the hinge region of Itk, and it also revealed a KSP, which could be used to improve potency and selectivity (80)(81)(82). Subsequently, biaryl-thiopene containing aminobenzimidazole compounds were screened to identify lead compounds that bound this KSP in Itk (83). This class of compounds has demonstrated efficacy in an in vivo mouse model when administered orally (84).…”

Section: Small Molecule Inhibitors Of Itkmentioning

confidence: 98%

Structure and function of Tec family kinase Itk

Kannan

August

2011

BioMolecular Concepts

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Itk is a member of the Tec family of kinases that is expressed predominantly in T cells. Itk regulates the T cell receptor signaling pathway to modulate T cell development and T helper cell differentiation, particularly Th2 differentiation. Itk is also important for the development and function of iNKT cells. In this review we discuss current progress on our understanding of the structure, activation and signaling pathway of Itk, in addition to inhibitors that have been developed, which target this kinase. We also place in context the function of Itk, available inhibitors and potential use in treating disease.

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“…These compounds were able to reduce the IL‐2 production with IC 50 of 240 to 690 nM in in vitro studies using human whole blood assays . Furthermore, studies in Balb/c mice indicated that the oral administration of these compounds inhibited the IL‐2 and IL‐4 secretion in response to the anti‐CD3 antibody in a dose dependent way with high potency . Efforts to improve the potency of these compounds have been achieved by modifying the thiophene ring through the attachment of aryl substituent .…”

Section: Introductionmentioning

confidence: 99%

Insight into the structural requirements of benzimidazole derivatives as interleukin‐2 inducible t‐cell kinase inhibitors by computational explorations

Wang

et al. 2013

Int J of Quantum Chemistry

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In the present work, a set of ligand-and receptor-based 3D-QSAR models were developed to explore the structure-activity relationship of 109 benzimidazole-based interleukin-2-inducible T-cell kinase (ITK) inhibitors. In order to reveal the requisite 3D structural features impacting the biological activities, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking, and molecular dynamics were applied. The results showed that the ligand-based CoMFA model (Q 2 5 0.552, R IntroductionT cell, also known as T lymphocyte, is a type of white blood cell that is of key importance to the immune system. [1] T-cell plays a central role in cell-mediated immunity which can be found in nearly any tissue at any time. By the presence of a Tcell antigen receptor (TCR) on the cell surface, T-cells are distinguished from other lymphocytes like the B cells and natural killer cells (NK cells), but are most concentrated in the lymphoid organs.[1] The activation of T-cell is critical for the initiation and regulation of the immune response, which leads to the development of cell-mediated immune mechanisms through the action of cytotoxic T-cell as well as by the engagement of accessory cells including macrophages.[2]To activate T-cell, the recognition of TCR is a necessity [3] that it leads to the fast recruitment and activation of three kinds of nonreceptor tyrosine kinases, the Src, Syk, and Tec families. [4] Among the Tec family, the interleukin-2-inducible Tcell kinase (ITK), a nonreceptor tyrosine kinase expressed primarily in hematopoietic cells, serves as an important mediator of antigen receptor signaling in lymphocytes. [2] For ITK, significant attention has been given to its activation via TCR stimulation. Once activated, ITK undergoes cis autophosphorylation on Y180 in its SH3 domain, [2] and plays an important role in Tcell signaling and the production of various pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10, and IL-13. [5] Moreover, ITK has been shown to play an essential role in the development of T cell dependent late phase responses of allergic asthma. [6] In research with ITK deficient mice reduced lung inflammation, mucous production and airway hyper responsiveness were observed in an ovalbumin-induced allergic asthma model. [7] Similar results were reported with a selective ITK inhibitor, which indicated the important role of ITK kinase activity in inflammatory diseases. [8] Therefore, tyrosine kinase ITK is regarded as a promising and an excellent potential therapeutic target for T cell-mediated diseases. The earliest report of selective ITK inhibitors came from researchers at Bristol-Myers Squibb.[5] These inhibitors have been tested in vitro on the human Jurkat T cell line and shown to specifically inhibit ITK and block the tyrosine phosphorylation and activation of phospholipase-Cc1. [9] Although these inhibitors come in handy, more studies are needed to test their efficacy, stability, and ...

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Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design

Cited by 30 publications

References 21 publications

ITK Inhibitors in Inflammation and Immune-Mediated Disorders

ITK Inhibitors in Inflammation and Immune-Mediated Disorders

Structure and function of Tec family kinase Itk

Insight into the structural requirements of benzimidazole derivatives as interleukin‐2 inducible t‐cell kinase inhibitors by computational explorations

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