ArticlePharmaceuticals (Basel, Switzerland)2023
Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain.
Article in Pharmaceuticals (Basel, Switzerland), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
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- Synthesis of Novel Acetylene-Containing Phosphonates, Their Antiviral Activity, and Their Cytotoxicity to Different Cancer Cell Lines.Molecules (Basel, Switzerland) · 2026Article
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- Targeted Therapies in Myelofibrosis: Present Landscape, Ongoing Studies, and Future Perspectives.American journal of hematology · 2025Review
- Development of Dual Aurora-A and Aurora-B Degrading PROTACs forChemMedChem · 2025Article
- Biological Evaluations and Computer-Aided Approaches of Janus Kinases 2 and 3 Inhibitors for Cancer Treatment: A Review.Pharmaceutics · 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
- Structural Analysis of Janus Tyrosine Kinase Variants in Hematological Malignancies: Implications for Drug Development and Opportunities for Novel Therapeutic Strategies.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted in identification of 55 binders to the ATP-binding pocket of recombinant JAK2 JH2 V617F protein at a low hit rate of 0.05%, which indicates unique structural characteristics of the JAK2 JH2 ATP-binding pocket. Selected hits and structural analogs were further assessed for binding to JH2 and JH1 (kinase) domains of JAK family members (JAK1-3, TYK2) and for effects on MPN model cell viability. Crystal structures were determined with JAK2 JH2 wild-type and V617F. The JH2-selective binders were identified in diaminotriazole, diaminotriazine, and phenylpyrazolo-pyrimidone chemical entities, but they showed low-affinity, and no inhibition of MPN cells was detected, while compounds binding to both JAK2 JH1 and JH2 domains inhibited MPN cell viability. X-ray crystal structures of protein-ligand complexes indicated generally similar binding modes between the ligands and V617F or wild-type JAK2. Ligands of JAK2 JH2 V617F are applicable as probes in JAK-STAT research, and SAR optimization combined with structural insights may yield higher-affinity inhibitors with biological activity.
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