ArticleThe Journal of biological chemistry2013
Discovery of novel irreversible inhibitors of interleukin (IL)-2-inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 32 citations in OpenAlex.
- Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity.npj drug discovery · 2024Article
- Activation and inhibition of the C-terminal kinase domain of p90 ribosomal S6 kinases.Life science alliance · 2023Article
- Identification of Thiazolo[5,4-Cancers · 2022Article
- Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis.Nature communications · 2020Article
- Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.Cell chemical biology · 2019Article
- Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70.Molecules (Basel, Switzerland) · 2019Article
- The reactivity-driven biochemical mechanism of covalent KRASNature structural & molecular biology · 2018Article
- The natural sesquiterpene lactones arglabin, grosheimin, agracin, parthenolide, and estafiatin inhibit T cell receptor (TCR) activation.Phytochemistry · 2018Article
- Novel chloroacetamido compound CWR-J02 is an anti-inflammatory glutaredoxin-1 inhibitor.PloS one · 2017Article
- The Search for Covalently Ligandable Proteins in Biological Systems.Molecules (Basel, Switzerland) · 2016Article
- Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.The Journal of biological chemistry · 2015Article
- Targeting Interleukin-2-Inducible T-cell Kinase (ITK) in T-Cell Related Diseases.Postdoc journal : a journal of postdoctoral research and postdoctoral affairs · 2014Article
- Characterisation of a K390R ITK kinase dead transgenic mouse--implications for ITK as a therapeutic target.PloS one · 2014Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
IL-2-inducible tyrosine kinase (Itk) plays a key role in antigen receptor signaling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted cysteine 442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by x-ray crystallography and enzymology while demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate, and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models.
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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.