ArticleJournal of medicinal chemistry2024
Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity.
Article in Journal of medicinal chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Large-scale comparative virtual screening identifies novel molecular targets underlying the multi-target activity of quercetin in psoriasis.Inflammopharmacology · 2026Article
- Base-Promoted Benzylic C-H Amination Reactions Across a Wide pKa Spectrum Enabled by 2-Halobenzofuran and -Indole Oxidants.Journal of the American Chemical Society · 2026Article
- Structural insights into multitargetingMicrobiology spectrum · 2026Article
- Review
- In-silico Exploration of the Possible Prolactin Pathway Related Targets of B. Monnieri against Triple Negative Breast Cancer: Selection of the Best Target Ligand Combination.Cell biochemistry and biophysics · 2026Article
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- Rapid and durable recovery of immune effector cells in myelofibrosis patients treated with momelotinib.Haematologica · 2026Article
- Allosteric inhibition of JAK2 with lysine-reactive compounds that bind the pseudokinase domain.European journal of medicinal chemistry · 2026Article
- A novel Ru(II) complex with pyrene-1-carbaldehyde hydrazone: structural, electronic, theoretical, and biological studies.Frontiers in chemistry · 2026Article
- Stability-Driven Pose Prediction and Ligand Design via Contact Persistence Analysis from Molecular Dynamics Simulations.Computational and structural biotechnology journal · 2026Article
- Identification of Novel JAK2 Inhibitors from Amino Derivatives of Epoxyalantolactone: In Silico and In Vitro Studies.International journal of molecular sciences · 2025Article
- Water Extract ofInternational journal of molecular sciences · 2025Article
- Molecular chameleons adaptability in target binding.Structural dynamics (Melville, N.Y.) · 2025Article
- Application of Free Energy Perturbation (FEP) Methodology for Predicting the Binding Affinity of Macrocyclic JAK2 Inhibitor Analogues of Pacritinib.ACS medicinal chemistry letters · 2025Article
- Impact of Ruxolitinib Interactions on JAK2 JH1 Domain Dynamics.International journal of molecular sciences · 2025Article
- JAK inhibitor selectivity: new opportunities, better drugs?Nature reviews. Rheumatology · 2024Review
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Janus kinase 2 (JAK2) plays a critical role in orchestrating hematopoiesis, and its deregulation leads to various blood disorders, most importantly myeloproliferative neoplasms (MPNs). Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. The development of next-generation JAK2 inhibitors is hampered by the lack of comparative functional analysis and knowledge of the molecular basis of their selectivity. Here, we provide mechanistic profiling of the four approved and six clinical-stage JAK2 inhibitors and connect selectivity data with high-resolution structural and thermodynamic analyses. All of the JAK inhibitors potently inhibited JAK2 activity. Inhibitors differed in their JAK isoform selectivity and potency for erythropoietin signaling, but their general cytokine inhibition signatures in blood cells were comparable. Structural data indicate that high potency and moderate JAK2 selectivity can be obtained by targeting the front pocket of the adenosine 5'-triphosphate-binding site.
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