ArticleCell chemical biology2023
New scaffolds for type II JAK2 inhibitors overcome the acquired G993A resistance mutation.
Article in Cell chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it, 11 citations in OpenAlex.
- A meta-analysis of diagnostic challenges in Ph-like ALL at baseline: early detection strategies for personalized therapeutic interventions.International journal of hematology · 2025Pooled it
- Large-scale comparative virtual screening identifies novel molecular targets underlying the multi-target activity of quercetin in psoriasis.Inflammopharmacology · 2026Article
- Review
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- 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
- The role of advanced diagnostics on precision medicine in hemato oncology.Discover oncology · 2025Review
- Pharmacophore Modeling of Janus Kinase Inhibitors: Tools for Drug Discovery and Exposition Prediction.Molecules (Basel, Switzerland) · 2025Article
- Bridging the Gap: Cost-Effective Strategies for Detecting Ph-Like B-Lineage ALL in Resource-Limited Settings.Molecular diagnosis & therapy · 2025Review
- JAK inhibitor withdrawal causes a transient pro-inflammatory cascade: A potential mechanism for major adverse cardiac events.PloS one · 2025Article
- 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
Corrections and comments
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Authors and funding
25 authors at 7 institutions in 2 countries.
Funding
Abstract
Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the "DFG-out" conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.
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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.