ArticleNature chemical biology2022
Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine.
Article in Nature chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 75 citations in OpenAlex.
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- A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease.Journal of the American Chemical Society · 2026Article
- Posttranslational modifications remodel proteome-wide ligandability.Nature chemical biology · 2026Article
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease ACTMAP.bioRxiv : the preprint server for biology · 2026Article
- Rus-GXF, a ruscogenin glycoside, binds to the ADP-binding domain of JAK1 to prevent inflammation and barrier damage in acute lung injury.Frontiers in pharmacology · 2026Article
- Targeting the Reactive Proteome: Recent Advances in Activity-Based Protein Profiling and Probe Design.Biomolecules · 2025Review
- Apigenin regulates CCR5/JAK1/STAT1/MMPs signaling to alleviate secondary brain injury after intracerebral hemorrhage and its enhanced delivery via targeted nanoparticles.Journal of nanobiotechnology · 2025Article
- Tryptoline Stereoprobe Elaboration Identifies Inhibitors of the GRPEL1-HSPA9 Chaperone Complex.bioRxiv : the preprint server for biology · 2025Article
- Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets.Biomolecules · 2025Review
- Proteome-wide ligandability maps of drugs with diverse cysteine-reactive chemotypes.Nature communications · 2025Article
- Delineating cysteine-reactive compound modulation of cellular proteostasis processes.Nature chemical biology · 2025Article
- An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes.Nature chemical biology · 2025Article
- Pyrazoline Derivatives: Exploring the Synthesis and Development of New Ligands for Anti-Cancer Therapy.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2025Review
- JAK inhibitor selectivity: new opportunities, better drugs?Nature reviews. Rheumatology · 2024Review
- Multi-tiered chemical proteomic maps of tryptoline acrylamide-protein interactions in cancer cells.Nature chemistry · 2024Article
- JAK2 inhibitors for the treatment of Philadelphia-negative myeloproliferative neoplasms: current status and future directions.Molecular diversity · 2024Review
- Ligand discovery by activity-based protein profiling.Cell chemical biology · 2024Review
- Chemical Proteomics-Guided Discovery of Covalent Ligands for Cancer Proteins.Annual review of cancer biology · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
19 authors at 3 institutions in 1 country.
Funding
Abstract
The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as 'silent' ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.
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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.