ITK Inhibitors in Inflammation and Immune-Mediated Disorders

Abstract

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.

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

“…Specifically, Th1 cells express both ITK and RLK, whereas Th2 cells express only ITK. This is consistent with early studies with ITK knock-out mice that show that Th2-and IL-4-dependent disease processes, such as ovalbumin-induced asthma, are blocked by ITK deletion, whereas Th1 responses remain intact, presumably due to redundancy of RLK signaling (14,48). RLK expression in Th17 cells is not well studied, but mice that have deletions of both kinases show profound defects in Th17 differentiation and function, a finding that was confirmed in our studies using human Th17 cells (9).…”

Tec family kinases Itk and Rlk / Txk in T lymphocytes: cross‐regulation of cytokine production and T‐cell fates

“…Despite uncertainties in the mechanisms behind these in vivo observations, it remains clear that mutation of Itk profoundly affects Th2 responses in vivo . For this reason, numerous drug companies have considered Itk as a potential therapeutic target for asthma and other diseases of hypersensitivity [20].…”

Tec family kinases: Itk signaling and the development of NKT αβ and γδ T cells

“…Future experiments determining whether the same signaling pathway is used differentially by these different T‐cell populations will be very informative. Nevertheless, these findings have important implications for the potential use of Itk inhibitors in various inflammatory diseases [2].…”

“…Interleukin‐2‐inducible T‐cell kinase (Itk) is a member of the Tec family of nonreceptor protein tyrosine kinases which includes Rlk and Tec, and is important for effective signaling through the T‐cell receptor (TCR) [1,2]. There are additional Tec family kinases that signal from other receptors and have essential functions in other cell types, and these are reviewed in the accompanying minireviews [3].…”