5-Aminomethylbenzimidazoles as potent ITK antagonists

Riether, Doris; Zindell, Renée; Kowalski, Jennifer A.; Cook, Brian N.; Bentzien, Jörg; Lombaert, Stéphane De; Thomson, D. S.; Kugler, Stanley; Skow, Donna; Martin, Leigh R.; Raymond, E.; Khine, Hnin Hnin; O’Shea, Kathy; Woska, Joseph R.; Jeanfavre, Deborah D.; Sellati, Rosemarie; Ralph, Kerry L. M.; Ahlberg, Jennifer; Labissiere, Gabriel; Kashem, Mohammed A.; Pullen, Steven S.; Takahashi, Hidenori

doi:10.1016/j.bmcl.2009.02.012

Cited by 39 publications

(36 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although there are a number of potent in vitro Itk inhibitors exemplified in the literature, none have been used to address the question of T H subtype specificity, although a few studies have gone on to describe in vivo activity (11,38). However, there have been no reported studies investigating the inhaled route of delivery.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket

Harling¹,

Deakin²,

Campos³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:Itk is considered an important target for anti-inflammatory drug discovery, particularly asthma. Results: We have designed an irreversible covalent inhibitor of the kinase by targeting Cys-442 in the ATP pocket. Conclusion: We have produced a potent, selective inhibitor with a long duration of action. Significance: We describe a novel drug discovery strategy with specific design features for inhaled delivery.

show abstract

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket

Harling¹,

Deakin²,

Campos³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Cells were then harvested, stained, and analyzed by flow cytometry. The ITK inhibitor, 10n (31), was synthesized at the National Institute of Health's Chemical Genomics Center and dissolved in DMSO at 100 mM, before dilution into cell culture media at the indicated working concentrations.…”

Section: Methodsmentioning

confidence: 99%

“…To test this prediction, we stimulated naive OT-I WT CD8 + T cells with high or low concentrations of CD3/ CD28 antibodies in the presence of a small-molecule inhibitor of ITK, 10n (31). As shown in Fig.…”

Section: Itk Inhibition Synergizes With Il-4 To Promote Eomes Up-regumentioning

confidence: 99%

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation

Nayar

Enos

Prince

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

113

View full text Add to dashboard Cite

CD8 + T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of “innate” T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (TCR) signaling pathway produce increased numbers of innate CD8 + T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor, Eomesodermin (Eomes). One component of this altered development is a non-CD8 + T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8 + T cells might also contribute to this pathway, we investigated the role of the transcription factor, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8 + T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8 + T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8 + T cells.

show abstract

“…Inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, is specifically expressed in T-cells (13); therefore, Runx3 may be a downstream transcription factor of ITK in signaling pathways that mediate asthma. Genistein, which is an interleukin-2-ITK inhibitor, has been previously demonstrated to decrease airway inflammation in allergic asthma (14), which was used to support the hypothesis that Runx3 is a downstream transcription of ITK signaling pathways.…”

Section: Introductionmentioning

confidence: 90%

“…These findings suggested that Runx3 may be phosphorylated by ITK, resulting in the exclusion of Runx3 from the nucleus. Therefore, in the present study ITK was inhibited in vitro by using a selective ITK inhibitor, 5-(aminomethyl)benzimidazole (14), which consequently reactivated the Runx3 protein by increasing the nuclear expression of Runx3. Following the administration of 5-(aminomethyl) benzimidazole, IL-4 and IFN-γ release in response to OVA was restored to that in the control group, exhibiting a balance of Th1/Th2 phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Mislocalization of Runt-related transcription factor 3 results in airway inflammation and airway hyper-responsiveness in a murine asthma model

Zhou

Zhu

Bian

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. The Runt-related transcription factor (RUNX) gene family consists of three members, RUNX1, -2 and -3, which heterodimerize with a common protein, core-binding factor β, and contain the highly conserved Runt-homology domain. RUNX1 and -2 have essential roles in hematopoiesis and osteogenesis. Runx3 protein regulates cell lineage decisions in neurogenesis and thymopoiesis. The aim of the present study was to determine the expression features of the Runx3 protein in a murine asthma model. In vivo, Runx3 protein and mRNA were found to be almost equivalently expressed in the murine lung tissue of the control, ovalbumin (OVA) and genistein groups; however, the nuclear Runx3 protein was abated in lung tissue in OVA-immunized and challenged mice. Following treatment with genistein, which is a flavonoid previously demonstrated to decrease airway inflammation in asthma, the allergic airway inflammation and airway hyper-responsiveness were attenuated and the Runx3 protein tended to augment in the nucleus. These results were further determined in vitro. These results indicated that the mislocalization of Runx3 protein is a molecular mechanism of allergic inflammation and airway hyper-responsiveness in a murine asthma model.

show abstract

5-Aminomethylbenzimidazoles as potent ITK antagonists

Cited by 39 publications

References 11 publications

Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket

Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation

Mislocalization of Runt-related transcription factor 3 results in airway inflammation and airway hyper-responsiveness in a murine asthma model

Contact Info

Product

Resources

About

5-Aminomethylbenzimidazoles as potent ITK antagonists

Cited by 39 publications

References 11 publications

Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket

Discovery of Novel Irreversible Inhibitors of Interleukin (IL)-2-inducible Tyrosine Kinase (Itk) by Targeting Cysteine 442 in the ATP Pocket

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 + T-cell differentiation

Mislocalization of Runt-related transcription factor 3 results in airway inflammation and airway hyper-responsiveness in a murine asthma model

Contact Info

Product

Resources

About

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation