Selective Targeting of JAK2 V617F Mutation in Hematologic Malignancies with LY2784544: A Promising Therapeutic Approach

The JAK2-V617F mutation is a frequent genetic alteration in BCR/ABL-negative myeloproliferative neoplasms (MPNs), prevalent in 95% of polycythemia vera (PV) patients and about 60% of those with essential thrombocythemia (ET) or primary myelofibrosis (PMF). This mutation leads to a constitutively active JAK2 V617F kinase, making it a promising target for MPN treatment. LY2784544, a novel small molecule inhibitor, has been shown to selectively target the JAK2 V617F mutation, and its efficacy was tested in both in vitro and in vivo models.

In the in vitro studies using Ba/F3 cells, LY2784544 significantly suppressed JAK2 V617F-STAT5 signaling at a substantially lower concentration compared to its effect on wild type JAK2-STAT5 signaling. The inhibitor was also selective in curbing JAK2 V617F-driven cell proliferation and induced apoptosis effectively. In contrast, it displayed lower potency in inhibiting IL-3-dependent cell proliferation and IL-2 dependent JAK3-STAT5 signaling.

In vivo experiments with a JAK2 V617F-induced ascites tumor model in SCID mice demonstrated that LY2784544 potently inhibited STAT5 phosphorylation with a Threshold Effective Dose 50 (TED50) of 12.7 mg/kg. The drug also notably reduced tumor burden in the JAK2 V617F-induced MPN model, with a TED50 of 13.7 mg/kg after a 14-day oral treatment, indicating its efficacy through the inhibition of the JAK2 V617F-STAT5 pathway. Notably, LY2784544 selectively targeted tumor cells without impacting CD71/Ter119 positive erythroid progenitor cells in the spleens of treated mice.

The findings highlight the potential of LY2784544 as a JAK2 V617F selective therapy that could induce apoptosis in malignant JAK2 V617F clones while sparing normal hematopoietic progenitor cells. These promising results have supported the progression of LY2784544 into a phase I clinical trial for MPNs. The study authors are affiliated with Eli Lilly and Company.