Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis

Abstract

ITK (IL-2-inducible tyrosine kinase) belongs to the Tec family kinases and is mainly expressed in T cells. It is involved in TCR signalling events driving processes like T cell development as well as Th2, Th9 and Th17 responses thereby controlling the expression of pro-inflammatory cytokines. Studies have shown that ITK is involved in the pathogenesis of autoimmune diseases as well as in carcinogenesis. The loss of ITK or its activity either by mutation or by the use of inhibitors led to a beneficial outcome in experimental models of asthma, inflammatory bowel disease and multiple sclerosis among others. In humans, biallelic mutations in the ITK gene locus result in a monogenetic disorder leading to T cell dysfunction; in consequence, mainly EBV infections can lead to severe immune dysregulation evident by lymphoproliferation, lymphoma and hemophagocytic lymphohistiocytosis. Furthermore, patients who suffer from angioimmunoblastic T cell lymphoma have been found to express significantly more ITK. These findings put ITK in the strong focus as a target for drug development.

C-5 Aryl Substituted Azaspirooxindolinones Derivatives: Synthesis and Biological Evaluation as Potential Inhibitors of Tec Family Kinases

“…The active compounds 11 and 12 displayed a higher activity against ITK positive lines and moderate activity in BTK lines, whereas 14 was highly active in BTK than ITK cell lines. Members of the Tec kinase family share similarities in structure, consisting of PH domain, SH3 domain, SH2 domain and kinase domain [10]. The selectivity of active compounds against ITK and other members of the Tec kinase family is currently being planned for the identified active compounds.…”

“…The interleukin-2-inducible kinase (ITK) is a non-receptor protein tyrosine kinase that belongs to the Tec kinase family [10]. Although predominantly expressed in T-cell lineages, natural killer cells and mast cells are also known to express ITK [10].…”

“…The interleukin-2-inducible kinase (ITK) is a non-receptor protein tyrosine kinase that belongs to the Tec kinase family [10]. Although predominantly expressed in T-cell lineages, natural killer cells and mast cells are also known to express ITK [10]. By modulating calcium signalling, ITK controls the activity and translocation of transcription factors like NFAT and NFκB [11].…”

“…PRN694 is a potential drug for preventing colitis disease and psoriasis therapy [28]. Although there is tremendous interest in ITK as a drug target, only a few novel ITK inhibitors exist in preclinical and clinical trials [10]. Currently, ibrutinib is the only approved treatment for chronic lymphocytic leukaemia and mantle B-cell lymphoma in the European Union since 2012 [29].…”

“…1). Next, the second series of eleven compounds (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) were prepared based on compound III and IV to evaluate the importance of carboxylic acid substituents on piperidine nitrogen by the conventional acid-amine coupling method. Altogether, we have synthesised nineteen new azaspiroindolinones and evaluated in vitro anticancer activity against a panel of ITK and BTK cell lines.…”