Pearson, S., Blance, R., Yan, F., Hsieh, Y.-C., Geary, B., Amaral, F. M. R., Somervaille, T. C. P., Kirschner, K. , Whetton, A. D. and Pierce, A. (2023) Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients. PLoS ONE, 18(5), e0286412. (doi: 10.1371/journal.pone.0286412) (PMID:37253035) (PMCID:PMC10228771)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | ADW and AP received awards from Blood Cancer UK (grants 13005 and 19007). TS and FA are supported by Cancer Research UK (grant C5759/A20971 and C5759/A27412. KK was funded by a John Goldman Fellowship sponsored by Leukaemia UK (2019/JGF/003) and CRUK Glasgow Centre funding (C7932/A25142) and CRUK Scotland Centre funding (CTRQQR-2021\100006). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Yan, Fei and Kirschner, Dr Kristina and Hsieh, Dr Ya-Ching |
| Creator Roles: | Yan, F.Data curation, Formal analysis, Investigation, Writing – review and editing Hsieh, Y.-C.Formal analysis, Investigation, Writing – review and editing Kirschner, K.Formal analysis, Funding acquisition, Resources, Supervision, Writing – review and editing |
| Authors: | Pearson, S., Blance, R., Yan, F., Hsieh, Y.-C., Geary, B., Amaral, F. M. R., Somervaille, T. C. P., Kirschner, K., Whetton, A. D., and Pierce, A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | PLoS ONE |
| Publisher: | Public Library of Science |
| ISSN: | 1932-6203 |
| ISSN (Online): | 1932-6203 |
| Copyright Holders: | Copyright © 2023 Pearson et al. |
| First Published: | First published in PLoS ONE 18(5): e0286412 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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