Researchers from the United Kingdom identified CBL0137 as a candidate targeting Jak2 mutation-driven malignancies by reanalyzing pre-existing proteomic datasets. Their aim was to identify perturbed biochemical pathways and their associated drugs/inhibitors that could be used as novel therapies.
The team led by Andrew Pierce, PhD, from the Stem Cell and Leukaemia Proteomics Laboratory at University of Manchester tested the activity of CBL0137 in primary patient samples and mouse models of Jak2-mutated myeloproliferative neoplasms.
Read more about the etiology of MF
They found that CBL0137 preferentially targeted CD34-positive stem and progenitor cells from patients with myelofibrosis (MF).
The researchers also investigated the mechanism of action of CBL0137 in primary hemopoietic progenitor cells and showed that it was able to reduce splenomegaly as well as the number of reticulocytes in a transgenic mouse model of myeloproliferative neoplasms.
“Our study illustrates the potential of CBL0137 as a possible therapeutic agent for the treatment of [myeloproliferative neoplasms],” the researchers concluded.
The findings are published in PLOS ONE.
CBL0137 is a drug derived from curaxin, which targets the Facilitates Chromatin Transcription (FACT) complex on chromatin, thereby activating p53 and inhibiting NF-kB. It has been shown to have antitumor activity, and it is currently being tested in phase 1 clinical trials in solid tumors and hematological malignancies, such as acute myeloid leukemia and chronic lymphocytic leukemia.
There are 4 main types of myeloproliferative neoplasms, one of which is MF where early hematopoietic stem cells undergo genetic mutations that lead to increased survival and clonal reproduction.
Around half of patients with primary MF have a mutation in the Jak2 gene, which disrupts cellular regulation.
Treatment with JAK2 inhibitors such as ruxolitinib can be beneficial in some patients with MF, but new therapies targeting the underlying cause of the disease are still needed.
Pearson S, Blance R, Yan F, et al. Identification of curaxin as a potential new therapeutic for JAK2 V617F mutant patients. PLoS One. Published online May 30, 2023. doi:10.1371/journal.pone.0286412