Itk inhibitors: a patent review

Lo, Ho Yin

doi:10.1517/13543771003674409

Cited by 24 publications

(17 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We are currently investigating rational treatment combinations between ITK inhibitors and standard treatments for metastatic melanoma in various preclinical melanoma models that may serve as the basis for future clinical trials in metastatic melanoma. Besides BI 10N, several other ITK inhibitors previously have been developed to target Th2 dominant autoimmune, inflammatory, and infectious diseases (48, 49). Notably, ibrutinib (IMBRUVICA, Pharmacyclics, Inc.), an irreversible inhibitor of BTK and ITK (50), has been granted approval by the U.S. Food and Drug Administration.…”

Section: Discussionmentioning

confidence: 99%

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

Carson

Moschos

Edmiston

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Interleukin-2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared to nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. Experimental Design An ITK specific monoclonal antibody was used to probe sections from de-identified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by immunohistochemistry. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. Results ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacological inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0/G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten null/Braf V600E) melanomas. Conclusions We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility.

show abstract

Section: Discussionmentioning

confidence: 99%

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

Carson

Moschos

Edmiston

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Tec kinases are being considered as targets for the treatments of a number of diseases and selective inhibitors targeting ITK and the related kinase BTK have been developed (58–62). As TXK is related to ITK and is also expressed in T cells, it is of interest to determine if this kinase has overlapping function.…”

Section: Discussionmentioning

confidence: 99%

A Unique Role for ITK in Survival of Invariant NKT Cells Associated with the p53-Dependent Pathway in Mice

Qian

Huang

Bai

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Invariant natural killer T (iNKT) cells play important roles in the immune response. ITK and TXK/RLK are Tec family kinases that are expressed in iNKT cells, with the expression level of ITK about 7-fold higher than that of TXK. Itk−/− mice have reduced iNKT cell frequency and numbers, with defects in development and cytokine secretion, which are exacerbated in the Itk/Txk DKO mice. By contrast, there is no iNKT cell defect in Txk−/− mice. To determine whether ITK and TXK play distinct roles in iNKT cell development and function, we examined mice that over express TXK in T cells to similar levels as Itk. Over expression of TXK rescues the maturation and cytokine secretion of Itk−/− iNKT cells, as well as altered expression of transcription factors T-bet, eomesodermin and PLZF. By contrast, the increased apoptosis observed in Itk−/− splenic iNKT cells is not affected by TXK over expression, likely due to lack of effect on the elevated expression of p53 regulated pro-apoptotic pathways Fas, Bax and Bad in those cells. Supporting this idea, p53−/− and Bax−/− mice have increased splenic iNKT cells. Our results suggest that TXK plays an overlapping role with ITK in iNKT cell development and function, but that ITK also has a unique function in the survival of iNKT cells, likely via a p53 dependent pathway.

show abstract

“…However, more recent exciting findings suggest that Rapamycin may be able to manipulate CD8 + T cell responses, enhancing long term development of CD8 + memory T cells, In addition, Rapamycin may be able to alter the development of CD4 + T helper subsets (Th1/2/17/Treg) (Waickman and Powell, 2012, Chi, 2012). More recent efforts have focused on targeted ZAP-70, Itk, PI3K, and MAPK (Hirabayashi et al, 2009, Lo, 2010, Norman, 2011, Chung, 2011, Trujillo, 2011). Expression of some of these targets such as ZAP-70, Lck, Fyn, and Itk are T cell specific or selective and so are much more likely to have specific effects on T cells without affecting other cell types.…”

Section: Associated Pathologies and Therapeutic Implicationsmentioning

confidence: 99%

Signal transduction via the T cell antigen receptor in naïve and effector/memory T cells

Kannan

Huang

et al. 2012

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

T cells play an indispensable role in immune defense against infectious agents, but can also be pathogenic. These T cells develop in the thymus, are exported into the periphery as naïve cells and participate in immune responses. Upon recognition of antigen, they are activated and differentiate into effector and memory T cells. While effector T cells carry out the function of the immune response, memory T cells can last up to the life time of the individual, and are activated by subsequent antigenic exposure. Throughout this life cycle, the T cell uses the same receptor for antigen, the T cell Receptor, a complex multi-subunit receptor. Recognition of antigen presented by peptide/MHC complexes on antigen presenting cells unleashes signaling pathways that control T cell activation at each stage. In this review, we discuss the signals regulated by the T cell receptor in naïve and effector/memory T cells.

show abstract

Itk inhibitors: a patent review

Cited by 24 publications

References 29 publications

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma

A Unique Role for ITK in Survival of Invariant NKT Cells Associated with the p53-Dependent Pathway in Mice

Signal transduction via the T cell antigen receptor in naïve and effector/memory T cells

Contact Info

Product

Resources

About