Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients

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  • Stella Pearson
    University of Manchester
  • Rognvald Blance
    University of Manchester
  • Fei Yan
    University of Glasgow
  • Ya-Ching Hsieh
    University of Glasgow
  • Bethany Geary
    University of Manchester
  • Fabio M. R. Amaral
    Cancer Research UK
  • Tim C. P. Somervaille
    Cancer Research UK
  • Kristina Kirschner
    University of Glasgow
  • Anthony D. Whetton
    University of Manchester
  • Andrew Pierce
    University of Manchester
Myelofibrosis is a myeloproliferative neoplasm (MPN) which typically results in reduced length and quality of life due to systemic symptoms and blood count changes arising from fibrotic changes in the bone marrow. While the JAK2 inhibitor ruxolitinib provides some clinical benefit, there remains a substantial unmet need for novel targeted therapies to better modify the disease process or eradicate the cells at the heart of myelofibrosis pathology. Repurposing drugs bypasses many of the hurdles present in drug development, such as toxicity and pharmacodynamic profiling. To this end we undertook a re-analysis of our pre-existing proteomic data sets to identify perturbed biochemical pathways and their associated drugs/inhibitors to potentially target the cells driving myelofibrosis. This approach identified CBL0137 as a candidate for targeting Jak2 mutation-driven malignancies. CBL0137 is a drug derived from curaxin targeting the Facilitates Chromatin Transcription (FACT) complex. It is reported to trap the FACT complex on chromatin thereby activating p53 and inhibiting NF-kB activity. We therefore assessed the activity of CBL0137 in primary patient samples and murine models of Jak2-mutated MPN and found it preferentially targets CD34+ stem and progenitor cells from myelofibrosis patients by comparison with healthy control cells. Further we investigate its mechanism of action in primary haemopoietic progenitor cells and demonstrate its ability to reduce splenomegaly and reticulocyte number in a transgenic murine model of myeloproliferative neoplasms.


  • Animals, Chromatin, Humans, Janus Kinase 2/metabolism, Mice, Mutation, Myeloproliferative Disorders/drug therapy, Primary Myelofibrosis/drug therapy, Proteomics, Quality of Life
Original languageEnglish
Article number0286412
Number of pages16
JournalPLoS ONE
Issue number5
Publication statusPublished - 30 May 2023
Externally publishedYes

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