PIM kinases (the proviral integration site of the Moloney leukemia virus) are a family of serine / threonine protein kinases with roles in cell development, immune regulation, and tumorigenesis. Early studies of the original Pim-1 led to the discovery of an oncogenic role of the Pim-1 family in lymphoma.
Although Pim-2 has only 55% amino acid identity with Pim-1, it is thought to be a compensation protein for Pim-1 because it has a very similar kinase domain. A third member of this family, pim-3, was found to catalyze histone phosphorylation and autophosphorylation. All three Pim proteins can phosphorylate serine and threonine amino acids and can activate similar cellular pathways. This has led researchers to believe that a single Pim kinase is compensatory and therefore the loss of one Pim kinase can be mitigated by expression of another Pim kinase.
Researchers from the University of Kansas Medical Center recently published a review in Molecular Cancer titled "Targeting Pim kinases in hematological cancers: molecular and clinical review," which summarizes the molecular and clinical progress of targeting Pim kinase in hematological tumors
Decades of research have recognized the solid role of Pim kinase in lymphoproliferative disorders. Following JAK / STAT and tyrosine kinase receptor signaling, Pim kinase is frequently upregulated, regulating cell proliferation, survival, metabolism, cell transport, and signaling.
Targeting Pim kinase is an interesting approach because knockout of Pim kinase causes a non-lethal phenotype in vivo, suggesting that clinical inhibition of Pim may have fewer side effects. Furthermore, ATP binding sites provide unique properties that can be exploited for the development of small molecule inhibitors targeting one or all of the Pim isoforms.
This review further studies the Pim kinase expression and its association with hematological cancers. The current and past clinical trials and the in vitro properties of Pim kinase inhibitors are reviewed and future directions are discussed. The present study suggests that Pim kinase inhibition may be the most valuable, when combined with multiple drug-targeted therapies.
Clinical trials using first-generation Pim inhibitors failed to significantly reduce the disease burden or reduce chemoresistance. Furthermore, higher doses of Pim inhibitors may have non-target effects and may lead to adverse effects, including cardiac events, gastrointestinal problems, febrile neutropenia, and rash.
Newer, highly specific inhibitors of Pim kinase, such as PIM447, UZANSERTIB, and TP-3654 could overcome these problems, allowing PIM targeting at lower concentrations. An alternative is to directly target Pim kinase by mAb Pim antibody treatment or indirect targeting of Pim kinase regulators. Pim-1 has been found on the cell surface of some leukemic cells that can lose proliferation when targeted by the mAb Pim-1 (mPim-1) therapy.
Future studies still need to delegate the specific roles of individual Pim isoforms, their downstream targets, and how to regulate Pim to more precisely improve treatment options. However, a large number of preclinical and clinical trials with Pim inhibitors have demonstrated the clinical implications of targeting the Pim pathway in lymphoproliferative disorders and solid tumors.
