Preclinical characterization of atiprimod, a novel JAK2 AND JAK3 inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Janus kinase (JAK) signaling pathways are crucial in hematopoiesis and immune responses.
• Constitutive activation of JAK2 (V617F) and JAK3 mutations drives various hematologic malignancies.
• Targeting JAK kinases offers a therapeutic strategy for these diseases.

Purpose of the Study:

• To evaluate the efficacy of the small molecule JAK2/JAK3 inhibitor atiprimod.
• To assess atiprimod's activity against cells with wild-type and mutant JAK2, and mutated JAK3.
• To investigate atiprimod's effects on signaling pathways and apoptosis in cancer cells and patient-derived progenitors.

Main Methods:

• In vitro studies using mouse FDCP-EpoR cells (JAK2 WT and V617F), human leukemia cell lines (SET-2, CMK).
• Assays included cell proliferation (IC50), Western blotting for signaling proteins (STAT3, STAT5, AKT), apoptosis markers (caspase-3, PARP cleavage, mitochondrial potential).
• Evaluation of atiprimod's effect on primary hematopoietic progenitors from polycythemia vera patients and healthy individuals.

Main Results:

• Atiprimod potently inhibited proliferation of JAK2 (V617F)-mutated cells (FDCP-EpoR V617F, SET-2) and JAK3-mutated cells (CMK) compared to JAK2 WT cells.
• Inhibition of JAK2 phosphorylation and downstream signaling (STAT3, STAT5, AKT) was observed in a dose- and time-dependent manner.
• Atiprimod induced apoptosis in JAK2 (V617F)-positive cells and reduced the JAK2 (V617F) mutant allele burden in patient-derived erythroid progenitors.

Conclusions:

• Atiprimod demonstrates significant anti-proliferative and pro-apoptotic activity against JAK2/JAK3-driven hematologic malignancies.
• The drug's efficacy in reducing mutant allele burden in patient samples is promising.
• These findings support the clinical investigation of atiprimod for hematologic malignancies with constitutive JAK2 or JAK3 activation.