TP-3654: PIM Kinase Inhibitor Showcasing Positive Results in Myelofibrosis Murine Model

Myelofibrosis (MF) is the most lethal of the myeloproliferative neoplasms (MPN), with the JAK2V617F mutation present in approximately half of MF patients. Although ruxolitinib, a JAK1/JAK2 inhibitor, is approved for MF treatment, it has not led to disease remission or reversal of fibrosis, highlighting the need for new targeted therapies.

This study explored the role of PIM1, which is upregulated in MPN/MF hematopoietic progenitor cells, and the potential of TP-3654, a second-generation pan-PIM kinase inhibitor, in treating MF. TP-3654 was found to significantly reduce the proliferation of JAK2V617F-expressing cells and induce apoptosis without affecting wild-type JAK2 cells. The drug also showed synergy with ruxolitinib in inducing apoptosis in JAK2V617F-expressing cells and inhibited the growth of MPN/MF CD34+ hematopoietic progenitor colonies.

In a JAK2V617F knock-in mouse model, TP-3654 monotherapy reduced white blood cell and neutrophil counts and spleen size in homozygous JAK2V617F mice. The combination of TP-3654 and ruxolitinib nearly normalized these parameters and significantly reduced fibrosis in the bone marrow and spleen, an effect not observed with ruxolitinib alone. TP-3654 was well-tolerated with no significant toxicity in wild-type mice.

RNA sequencing analysis indicated that TP-3654, alone or in combination with ruxolitinib, significantly downregulated genes related to TNFα and WNT signaling pathways. These findings suggest that TP-3654, either as a single agent or in combination with ruxolitinib, may offer a new therapeutic approach for the treatment of myelofibrosis.