ArticleThe Journal of biological chemistry2015
Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 51 citations in OpenAlex.
- Advances and Perspectives in the Treatment of T-PLL.Current hematologic malignancy reports · 2020Pooled it
- Review
- Discovery of an ITK and TRK kinase inhibitor for the potential topical treatment of atopic dermatitis.Nature communications · 2026Article
- The role of JAK3 and TEC family kinases in vitiligo pathogenesis.Frontiers in immunology · 2026Review
- Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines.Science signaling · 2025Article
- <italic>TXK</italic> Functional Variants Contribute to Asthma by Regulating Th1 and Th17 Cytokine Pathways.International archives of allergy and immunology · 2025Article
- Advancements in research on the cardiovascular toxicity caused by TEC family kinases inhibitors.Frontiers in pharmacology · 2025Review
- Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity.npj drug discovery · 2024Article
- Gene expression profiles associated with early relapse during first remission induction in canine multicentric high-grade B-cell lymphoma.The Journal of veterinary medical science · 2024Article
- Conformational Selectivity of ITK Inhibitors: Insights from Molecular Dynamics Simulations.Journal of chemical information and modeling · 2023Article
- Combinatorial inhibition of Tec kinases BTK and ITK is beneficial in ameliorating murine sclerodermatous chronic graft versus host disease.Bone marrow transplantation · 2023Article
- T-Cell Prolymphocytic Leukemia: Diagnosis, Pathogenesis, and Treatment.International journal of molecular sciences · 2023Review
- Regulation of Cx43 Gap Junction Intercellular Communication by Bruton's Tyrosine Kinase and Interleukin-2-Inducible T-Cell Kinase.Biomolecules · 2023Article
- Analysis of T-cell Receptor-Induced Calcium Influx in Primary Murine T-cells by Full Spectrum Flow Cytometry.Journal of visualized experiments : JoVE · 2022Article
- Novel T Follicular Helper-like T-Cell Lymphoma Therapies: From Preclinical Evaluation to Clinical Reality.Cancers · 2022Review
- Cytotoxic lymphocytes-related gene ITK from a systematic CRISPR screen could predict prognosis of ovarian cancer patients with distant metastasis.Journal of translational medicine · 2021Article
- Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia.International journal of molecular sciences · 2020Review
- Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis.Journal of molecular medicine (Berlin, Germany) · 2020Review
- Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
Abstract
Interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK or TXK) are essential mediators of intracellular signaling in both normal and neoplastic T-cells and natural killer (NK) cells. Thus, ITK and RLK inhibitors have therapeutic potential in a number of human autoimmune, inflammatory, and malignant diseases. Here we describe a novel ITK/RLK inhibitor, PRN694, which covalently binds to cysteine residues 442 of ITK and 350 of RLK and blocks kinase activity. Molecular modeling was utilized to design molecules that interact with cysteine while binding to the ATP binding site in the kinase domain. PRN694 exhibits extended target residence time on ITK and RLK and is highly selective for a subset of the TEC kinase family. In vitro cellular assays confirm that PRN694 prevents T-cell receptor- and Fc receptor-induced cellular and molecular activation, inhibits T-cell receptor-induced T-cell proliferation, and blocks proinflammatory cytokine release as well as activation of Th17 cells. Ex vivo assays demonstrate inhibitory activity against T-cell prolymphocytic leukemia cells, and in vivo assays demonstrate durable pharmacodynamic effects on ITK, which reduces an oxazolone-induced delayed type hypersensitivity reaction. These data indicate that PRN694 is a highly selective and potent covalent inhibitor of ITK and RLK, and its extended target residence time enables durable attenuation of effector cells in vitro and in vivo. The results from this study highlight potential applications of this dual inhibitor for the treatment of T-cell- or NK cell-mediated inflammatory, autoimmune, and malignant diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.