ArticleThe Journal of biological chemistry2015
Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol.
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 35 papers.
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Who cites it
35 citing papers in PubMed, 96 citations in OpenAlex.
- Large-scale comparative virtual screening identifies novel molecular targets underlying the multi-target activity of quercetin in psoriasis.Inflammopharmacology · 2026Article
- Effective virtual screening strategy toward JAK3 covalent inhibitors: combining multi‑conformational consensus calculation with covalent docking.Molecular diversity · 2026Article
- Anti-Cryptosporidium efficacy of BKI-1708, an inhibitor of Cryptosporidium calcium-dependent protein kinase 1.PLoS neglected tropical diseases · 2025Article
- Identification of novel covalent JAK3 inhibitors through consensus scoring virtual screening: integration of common feature pharmacophore and covalent docking.Molecular diversity · 2025Article
- Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action.ACS chemical biology · 2024Review
- Advances in covalent drug discovery.Nature reviews. Drug discovery · 2022Review
- Pharmacokinetic Optimization of Small Molecule Janus Kinase 3 Inhibitors to Target Immune Cells.ACS pharmacology & translational science · 2022Article
- Design of Rational JAK3 Inhibitors Based on the Parent Core Structure of 1,7-Dihydro-Dipyrrolo [2,3-b:3',2'-e] Pyridine.International journal of molecular sciences · 2022Article
- A Comprehensive Overview of Globally Approved JAK Inhibitors.Pharmaceutics · 2022Review
- Repurposing drug molecule against SARS-Cov-2 (COVID-19) through molecular docking and dynamics: a quick approach to pick FDA-approved drugs.Journal of molecular modeling · 2021Article
- Pyrrolopyrimidine Bumped Kinase Inhibitors for the Treatment of Cryptosporidiosis.ACS infectious diseases · 2021Article
- Generation of a chemical genetic model for JAK3.Scientific reports · 2021Article
- Synthesis, Docking, Computational Studies, and Antimicrobial Evaluations of New Dipeptide Derivatives Based on Nicotinoylglycylglycine Hydrazide.Molecules (Basel, Switzerland) · 2020Article
- Structure-Activity Relationship between Thiol Group-Trapping Ability of Morphinan Compounds with a Michael Acceptor and Anti-Molecules (Basel, Switzerland) · 2020Article
- Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome.Cell chemical biology · 2019Article
- Systematic Studies on the Protocol and Criteria for Selecting a Covalent Docking Tool.Molecules (Basel, Switzerland) · 2019Article
- Article
- Fine-Tuning Cytokine Signals.Annual review of immunology · 2019Review
- Essential Kinases and Transcriptional Regulators and Their Roles in Autoimmunity.Biomolecules · 2019Review
- Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis.ACS medicinal chemistry letters · 2019Article
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.
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Registered trials
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.