RARE DISEASE
Myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2
Myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2
Myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2
Drug discovery
2
drugs
With orphan designations
Overview
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene rearrangements (PDGFRA, PDGFRB, FGFR1, or JAK2) are rare, aggressive hematologic malignancies presenting as chronic eosinophilic leukemia, acute leukemias, or lymphomas. They arise from fusion genes causing constitutive tyrosine kinase activation, leading to eosinophil-driven organ damage and rapid progression without treatment [1][2][7][11].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,020 drug discovery papers about Myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,020 drug discovery papers about Myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Identification of Novel Small-Molecule Janus Kinase 1 and 2 Inhibitors Through Structure-Based Virtual Screening, In Vitro Assays, and Molecular Dynamics Simulations.
Janus kinases (JAKs) are central mediators of cytokine-driven signal transducer and activator of transcription (STAT) signaling, and dysregulation of the JAK-STAT axis is implicated in inflammatory, autoimmune, and neoplastic diseases. To identify new small-molecule inhibitors of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), we implemented an integrated virtual screening workflow combining structure-based docking and ligand-based prioritization using the InterBioScreen (IBS) compound library. A drug-likeness filter reduced 521,627 IBS molecules to 116,064 candidates, which were then docked into the ATP-binding sites of JAK1 (PDB ID: 4EI4) and JAK2 (PDB ID: 6VGL) using Glide SP; compounds were prioritized using docking score thresholds of <- 8.5 kcal/mol (JAK1) and <- 9.0 kcal/mol (JAK2), yielding 407 JAK1- and 298 JAK2-focused hits. Subsequent analysis shortlisted 42 candidates for enzymatic evaluation. In vitro kinase assays identified multiple nanomolar inhibitors, including compound 1-3 (IC50 = 0.032 μM) among the most potent for JAK1 and compound 2-8 (IC50 = 0.026 μM) for JAK2. Finally, 100 ns molecular dynamics (MD) simulations supported stable binding for representative complexes, with persistent hinge-region interactions for compound 1-3 in JAK1 (e.g., Glu957/Leu959) and compound 2-8 in JAK2 (e.g., Glu930/Leu932), consistent with a stable interaction network in the active site. Collectively, these results define validated IBS-derived hit scaffolds for further optimization and selectivity profiling toward JAK-targeted therapeutics.
2026-08-08 | Hierarchical mathematical modelling of patients with myeloproliferative neoplasms captures interferon-α treatment responses and allows for personalised and population predictions.
The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of haematological malignancies triggered by a driver mutation, most commonly the JAK2 V617F mutation, which is acquired in a haematopoietic stem cell. The diseases are characterised by an overproduction of myeloid cells and may result in severe complications such as thrombosis, myelofibrotic transition, and potentially progression to acute myeloid leukaemia. Treatment with interferon-α (IFN-α) can potentially deplete the disease-driving malignant stem cell population, thereby leading to long-term remission. We extend a mechanistic compartmental differential equation model of MPN progression to account for the effects of IFN-α treatment. In agreement with experimental mouse studies, we assume that IFN-α acts through effects on malignant stem cell differentiation and malignant progenitor and precursor cell apoptosis. We use a hierarchical Bayesian inference procedure to infer the drug response parameters of the model based on measurements of the JAK2 V617F variant allele frequency (VAF) for N=56 patients from the Danish DALIAH study, both on the individual and the population level, with 14 patients left out for subsequent testing. The model estimates are found to agree with data. The drug response parameters are found to act synergistically on the reduction of JAK2 VAF, with the model being able to capture qualitatively different types of treatment responses. Using the inferred information about the population distribution of drug response parameters is found to improve predictions compared to predictions without prior knowledge on a testing cohort. Such predictions may aid clinical decision-making regarding IFN-α treatment in patients with MPNs.
2026-07-14 | Uncompetitive Allosteric Inhibition of PTP1B by BP-1-102 Reveals a Potential Dual-Target Strategy toward the PTP1B-STAT3 Oncogenic Axis: Biochemical and Computational Evidence.
Selective PTP1B inhibitors paradoxically potentiate oncogenic STAT3 signaling by restoring JAK2 activity, underscoring the need for dual-target strategies. Here we report that BP-1-102, an orally bioavailable STAT3 SH2 domain inhibitor, also potently inhibits PTP1B with IC50 values of 5.32 μM (hPTP1B1-400) and 11.7 μM (hPTP1B1-285), with ≥37.7-fold selectivity over TCPTP. Kinetic analysis identified an uncompetitive mechanism, suggesting inhibitor binding to the enzyme-substrate complex at a site distal to the active site. Docking and 500 ns molecular dynamics simulations revealed a dual-anchor binding mode involving the 113-123 loop (Cys121) and the proline-rich C-terminal disordered region, a structural interface absent in TCPTP. Umbrella sampling confirmed favorable passive membrane permeability through a tumor-mimetic bilayer (ΔG = -13.83 kcal/mol). These results propose BP-1-102 as a candidate for dual-function inhibitor of the PTP1B-JAK2-STAT3 oncogenic axis, providing a physicochemical and mechanistic rationale for its further evaluation in tumors where both targets are coactivated.
2026-07-14 | Design, synthesis, and activity study of heterocyclic derivatives as JAK inhibitors.
The Janus kinase (JAK) family plays a central role in regulating inflammation and fibrosis through the JAK/STAT signaling pathway, making it an attractive therapeutic target for immune-mediated diseases. In the present study, structural modifications of the quinazoline core were systematically explored to identify potent JAK inhibitors. A CXCL10-based screening strategy identified compound 22a as a promising lead, exhibiting strong inhibitory activity in HaCaT cells with an IC50 value of 308 nM. Subsequent kinase assays demonstrated that compound 22a exhibits higher inhibitory potency toward JAK1 (IC50 = 37.86 nM) compared to JAK2 (IC50 = 102.5 nM), JAK3 (IC50 = 69.35 nM), and TYK2 (IC50 = 2142 nM). Mechanistic studies revealed a dose-dependent suppression of STAT1 phosphorylation, confirming inhibition of the JAK1/2-STAT1 signaling pathway. In addition, molecular docking and molecular dynamics simulations were performed to elucidate and validate the binding mode of compound 22a within the JAK1 active site. Collectively, these results indicate that the developed quinazoline derivatives represent promising leads for the further development of selective JAK1 inhibitors.
2026-07-07 | Janus kinase 2 activation loop as a regulator of catalysis and trans-activation.
Protein kinases regulate essential cellular processes such as apoptosis, proliferation, and growth. Precise regulation of kinase activity is critical for proper signal transduction and is often mediated by activation-loop phosphorylation. Janus kinases (JAKs) employ a unique regulatory mechanism: they remain autoinhibited by their pseudokinase domains until cytokine stimulation triggers dimerization and trans-phosphorylation of two activation-loop tyrosines. Despite its relevance for JAK inhibitor design, the molecular mechanism of JAK activation by activation-loop phosphorylation is not fully understood. Here, we show that phosphorylation of the JAK2 activation loop is essential for stabilizing substrate binding and in the absence of phosphorylation, the activation loop fails to bind substrates. Our findings reveal a unique regulatory role for the activation loop in JAK2, where phosphorylation enhances loop stability rather than inducing a major conformational change as in most protein kinases. In addition, the flexibility of the unphosphorylated activation loop allows conformational changes required for trans-phosphorylation during JAK activation. These insights provide a mechanistic basis for JAK activation and offer new insights for the development of JAK inhibitors.
2026-08-14 | Identification of Novel Small-Molecule Janus Kinase 1 and 2 Inhibitors Through Structure-Based Virtual Screening, In Vitro Assays, and Molecular Dynamics Simulations.
Janus kinases (JAKs) are central mediators of cytokine-driven signal transducer and activator of transcription (STAT) signaling, and dysregulation of the JAK-STAT axis is implicated in inflammatory, autoimmune, and neoplastic diseases. To identify new small-molecule inhibitors of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), we implemented an integrated virtual screening workflow combining structure-based docking and ligand-based prioritization using the InterBioScreen (IBS) compound library. A drug-likeness filter reduced 521,627 IBS molecules to 116,064 candidates, which were then docked into the ATP-binding sites of JAK1 (PDB ID: 4EI4) and JAK2 (PDB ID: 6VGL) using Glide SP; compounds were prioritized using docking score thresholds of <- 8.5 kcal/mol (JAK1) and <- 9.0 kcal/mol (JAK2), yielding 407 JAK1- and 298 JAK2-focused hits. Subsequent analysis shortlisted 42 candidates for enzymatic evaluation. In vitro kinase assays identified multiple nanomolar inhibitors, including compound 1-3 (IC50 = 0.032 μM) among the most potent for JAK1 and compound 2-8 (IC50 = 0.026 μM) for JAK2. Finally, 100 ns molecular dynamics (MD) simulations supported stable binding for representative complexes, with persistent hinge-region interactions for compound 1-3 in JAK1 (e.g., Glu957/Leu959) and compound 2-8 in JAK2 (e.g., Glu930/Leu932), consistent with a stable interaction network in the active site. Collectively, these results define validated IBS-derived hit scaffolds for further optimization and selectivity profiling toward JAK-targeted therapeutics.
2026-08-08 | Hierarchical mathematical modelling of patients with myeloproliferative neoplasms captures interferon-α treatment responses and allows for personalised and population predictions.
The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of haematological malignancies triggered by a driver mutation, most commonly the JAK2 V617F mutation, which is acquired in a haematopoietic stem cell. The diseases are characterised by an overproduction of myeloid cells and may result in severe complications such as thrombosis, myelofibrotic transition, and potentially progression to acute myeloid leukaemia. Treatment with interferon-α (IFN-α) can potentially deplete the disease-driving malignant stem cell population, thereby leading to long-term remission. We extend a mechanistic compartmental differential equation model of MPN progression to account for the effects of IFN-α treatment. In agreement with experimental mouse studies, we assume that IFN-α acts through effects on malignant stem cell differentiation and malignant progenitor and precursor cell apoptosis. We use a hierarchical Bayesian inference procedure to infer the drug response parameters of the model based on measurements of the JAK2 V617F variant allele frequency (VAF) for N=56 patients from the Danish DALIAH study, both on the individual and the population level, with 14 patients left out for subsequent testing. The model estimates are found to agree with data. The drug response parameters are found to act synergistically on the reduction of JAK2 VAF, with the model being able to capture qualitatively different types of treatment responses. Using the inferred information about the population distribution of drug response parameters is found to improve predictions compared to predictions without prior knowledge on a testing cohort. Such predictions may aid clinical decision-making regarding IFN-α treatment in patients with MPNs.
2026-07-14 | Uncompetitive Allosteric Inhibition of PTP1B by BP-1-102 Reveals a Potential Dual-Target Strategy toward the PTP1B-STAT3 Oncogenic Axis: Biochemical and Computational Evidence.
Selective PTP1B inhibitors paradoxically potentiate oncogenic STAT3 signaling by restoring JAK2 activity, underscoring the need for dual-target strategies. Here we report that BP-1-102, an orally bioavailable STAT3 SH2 domain inhibitor, also potently inhibits PTP1B with IC50 values of 5.32 μM (hPTP1B1-400) and 11.7 μM (hPTP1B1-285), with ≥37.7-fold selectivity over TCPTP. Kinetic analysis identified an uncompetitive mechanism, suggesting inhibitor binding to the enzyme-substrate complex at a site distal to the active site. Docking and 500 ns molecular dynamics simulations revealed a dual-anchor binding mode involving the 113-123 loop (Cys121) and the proline-rich C-terminal disordered region, a structural interface absent in TCPTP. Umbrella sampling confirmed favorable passive membrane permeability through a tumor-mimetic bilayer (ΔG = -13.83 kcal/mol). These results propose BP-1-102 as a candidate for dual-function inhibitor of the PTP1B-JAK2-STAT3 oncogenic axis, providing a physicochemical and mechanistic rationale for its further evaluation in tumors where both targets are coactivated.
2026-07-14 | Design, synthesis, and activity study of heterocyclic derivatives as JAK inhibitors.
The Janus kinase (JAK) family plays a central role in regulating inflammation and fibrosis through the JAK/STAT signaling pathway, making it an attractive therapeutic target for immune-mediated diseases. In the present study, structural modifications of the quinazoline core were systematically explored to identify potent JAK inhibitors. A CXCL10-based screening strategy identified compound 22a as a promising lead, exhibiting strong inhibitory activity in HaCaT cells with an IC50 value of 308 nM. Subsequent kinase assays demonstrated that compound 22a exhibits higher inhibitory potency toward JAK1 (IC50 = 37.86 nM) compared to JAK2 (IC50 = 102.5 nM), JAK3 (IC50 = 69.35 nM), and TYK2 (IC50 = 2142 nM). Mechanistic studies revealed a dose-dependent suppression of STAT1 phosphorylation, confirming inhibition of the JAK1/2-STAT1 signaling pathway. In addition, molecular docking and molecular dynamics simulations were performed to elucidate and validate the binding mode of compound 22a within the JAK1 active site. Collectively, these results indicate that the developed quinazoline derivatives represent promising leads for the further development of selective JAK1 inhibitors.
2026-07-07 | Janus kinase 2 activation loop as a regulator of catalysis and trans-activation.
Protein kinases regulate essential cellular processes such as apoptosis, proliferation, and growth. Precise regulation of kinase activity is critical for proper signal transduction and is often mediated by activation-loop phosphorylation. Janus kinases (JAKs) employ a unique regulatory mechanism: they remain autoinhibited by their pseudokinase domains until cytokine stimulation triggers dimerization and trans-phosphorylation of two activation-loop tyrosines. Despite its relevance for JAK inhibitor design, the molecular mechanism of JAK activation by activation-loop phosphorylation is not fully understood. Here, we show that phosphorylation of the JAK2 activation loop is essential for stabilizing substrate binding and in the absence of phosphorylation, the activation loop fails to bind substrates. Our findings reveal a unique regulatory role for the activation loop in JAK2, where phosphorylation enhances loop stability rather than inducing a major conformational change as in most protein kinases. In addition, the flexibility of the unphosphorylated activation loop allows conformational changes required for trans-phosphorylation during JAK activation. These insights provide a mechanistic basis for JAK activation and offer new insights for the development of JAK inhibitors.
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Drug Discovery Landscape
2 orphan drug designations for Myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2, including 1 approved therapy.
2 orphan drug designations for Myeloid/lymphoid neoplasms associated with eosinophilia and abnormality of PDGFRA, PDGFRB, FGFR1 or JAK2, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Pemigatinib | small molecules | EMA | 2019-10-17 | — | Incyte Biosciences Distribution B.V. |
pemigatinib [Pemazyre] | small molecules | FDA | 2019-08-21 | 2022-08-26 | Incyte Corporation |
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