ArticleScientific reports2015
Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance.
Article in Scientific reports, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Drug repurposing based on differentially expressed genes suggests drug combinations with possible synergistic effects in treatment of lung adenocarcinoma.Cancer biology & therapy · 2023Pooled it
- Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure.American journal of hematology · 2020Trial
- The Mechanisms of Resistance to JAK Inhibitors in Lymphoid Leukemias: A Scoping Review of Evidence from Preclinical Models and Case Reports.International journal of molecular sciences · 2025Article
- Glutamic Acid at Position 343 in PB2 Contributes to the Virulence of H1N1 Swine Influenza Virus in Mice.Viruses · 2025Article
- Chalcone-9: a novel inhibitor of the JAK-STAT pathway with potent anti-cancer effects in triple-negative breast cancer cells.Pharmacological reports : PR · 2025Article
- Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling.Nature communications · 2025Article
- Exploring novel furochochicine derivatives as promising JAK2 inhibitors in HeLa cells: Integrating docking, QSAR-ML, MD simulations, and experiments.Computational and structural biotechnology journal · 2025Article
- Type II mode of JAK2 inhibition and destabilization are potential therapeutic approaches against the ruxolitinib resistance driven myeloproliferative neoplasms.Frontiers in oncology · 2024Article
- Molecular biomarkers of leukemia: convergence-based drug resistance mechanisms in chronic myeloid leukemia and myeloproliferative neoplasms.Frontiers in pharmacology · 2024Review
- Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.Blood advances · 2023Article
- CoGT: Ensemble Machine Learning Method and Its Application on JAK Inhibitor Discovery.ACS omega · 2023Article
- Momelotinib is a highly potent inhibitor of FLT3-mutant AML.Blood advances · 2022Article
- The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia.Science advances · 2022Article
- Article
- Review
- An overview of kinase downregulators and recent advances in discovery approaches.Signal transduction and targeted therapy · 2021Review
- Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?Cancers · 2021Review
- Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia.NPJ precision oncology · 2021Article
- Structural Basis of Inhibition of DCLK1 by Ruxolitinib.International journal of molecular sciences · 2021Article
- Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications.Haematologica · 2021Review
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Authors and funding
11 authors.
Funding
Abstract
Emergence of genetic resistance against kinase inhibitors poses a great challenge for durable therapeutic response. Here, we report a novel mechanism of JAK2 kinase inhibition by fedratinib (TG101348) that prevents emergence of genetic resistance. Using in vitro drug screening, we identified 211 amino-acid substitutions conferring resistance to ruxolitinib (INCB018424) and cross-resistance to the JAK2 inhibitors AZD1480, CYT-387 and lestaurtinib. In contrast, these resistant variants were fully sensitive to fedratinib. Structural modeling, coupled with mutagenesis and biochemical studies, revealed dual binding sites for fedratinib. In vitro binding assays using purified proteins showed strong affinity for the substrate-binding site (Kd = 20 nM) while affinity for the ATP site was poor (Kd = ~8 μM). Our studies demonstrate that mutations affecting the substrate-binding pocket encode a catalytically incompetent kinase, thereby preventing emergence of resistant variants. Most importantly, our data suggest that in order to develop resistance-free kinase inhibitors, the next-generation drug design should target the substrate-binding site.
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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.