ArticleCancer discovery2012
Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent.
Article in Cancer discovery, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
79 citing papers in PubMed, 127 citations in OpenAlex.
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- A Scalable Design for Proximity-Inducing Molecules.bioRxiv : the preprint server for biology · 2026Article
- Article
- Revisiting Janus kinases as molecular drug targets for rheumatic diseases.Frontiers in medicine · 2026Review
- Effects of Methotrexate and Tofacitinib on Mitochondrial Function and Oxidative Stress in Human Synovial Cells In Vitro.International journal of molecular sciences · 2025Article
- Ruxolitinib mediated paradoxical JAK2 hyperphosphorylation is due to the protection of activation loop tyrosines from phosphatases.Leukemia · 2025Article
- Modulating JAK2/STAT3 signaling by quercetin in Qiling Baitouweng Tang: a potential therapeutic approach for diffuse large B-cell lymphoma.Molecular diversity · 2025Article
- Recent advances and future perspectives in small molecule JAK2 inhibitors.Future medicinal chemistry · 2025Review
- JAK inhibitor withdrawal causes a transient pro-inflammatory cascade: A potential mechanism for major adverse cardiac events.PloS one · 2025Article
- Investigational drugs in early phase trials for myelofibrosis.Expert opinion on investigational drugs · 2024Review
- Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity.Journal of medicinal chemistry · 2024Article
- Molecular basis of JAK2 activation in erythropoietin receptor and pathogenic JAK2 signaling.Science advances · 2024Article
- Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated molecular dynamics simulations: a dynamic odyssey.Journal of computer-aided molecular design · 2024Article
- Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms.Frontiers in oncology · 2024Article
- Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.Blood cancer discovery · 2023Article
- Molecular Dynamics and Machine Learning Give Insights on the Flexibility-Activity Relationships in Tyrosine Kinome.Journal of chemical information and modeling · 2023Article
- New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation.Cell chemical biology · 2023Article
- Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands.Journal of medicinal chemistry · 2022Article
- A Comprehensive Overview of Globally Approved JAK Inhibitors.Pharmaceutics · 2022Review
19 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
24 authors at 5 institutions in 2 countries.
Funding
Abstract
Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II inhibition acts in the opposite manner, leading to a loss of activation loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor-induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited.
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What OpenQuestion holds
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.