Targeting Pim kinases in hematological cancers: molecular and clinical review

Abstract

Decades of research has recognized a solid role for Pim kinases in lymphoproliferative disorders. Often up-regulated following JAK/STAT and tyrosine kinase receptor signaling, Pim kinases regulate cell proliferation, survival, metabolism, cellular trafficking and signaling. Targeting Pim kinases represents an interesting approach since knock-down of Pim kinases leads to non-fatal phenotypes in vivo suggesting clinical inhibition of Pim may have less side effects. In addition, the ATP binding site offers unique characteristics that can be used for the development of small inhibitors targeting one or all Pim isoforms. This review takes a closer look at Pim kinase expression and involvement in hematopoietic cancers. Current and past clinical trials and in vitro characterization of Pim kinase inhibitors are examined and future directions are discussed. Current studies suggest that Pim kinase inhibition may be most valuable when accompanied by multi-drug targeting therapy.

Clonal Relationship and Mutation Analysis in Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia Associated With Diffuse Large B-cell Lymphoma

“…52 PIM1 represents a serine/threonine kinase that acts in several signaling pathways regulating cell survival, metabolism, and cell proliferation. 53,54 Since PIM1 is a common off-target of activation-induced cytidine deaminase-mediated SHM in the role of these mutations in enhancing the oncogenic potential of PIM1 remains to be established. Besides the DLBCL occurrences that developed through LPL transformation, in 3 out of 13 LPL/WM patients (23%) clonally unrelated lymphomas were identified in one of the DLBCL biopsies, demonstrated by the presence of different dominant clonotypes for 2 or more IG targets.…”

Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles

“…From the involvement of PIM in multiple pathways and the resulting effects, it is evident that inhibiting a PIM target can impact cells at different stages of growth, thereby reducing the use of multiple drugs while improving their efficacy. The interplay between PIM and multiple pathways also indicates that the combination of PIM kinase inhibitors with other drugs is an important direction to consider, in order to target different cellular growth processes and enhance treatment outcomes and survival rates. − …”

Identification and assessment of new PIM2 inhibitors for treating hematologic cancers: A combined approach of energy‐based virtual screening and machine learning evaluation

“…[13][14][15] These factors exert an upregulatory effect on the expression of PIM2, primarily through the JAK/STAT pathway. [16][17][18] Heightened expression of PIM2 could significantly synergize with the overexpression of MYC in the hematopoietic lineage, thereby fostering MYC-driven tumors. [8,9] Additionally, when PIM2 is activated and highly expressed, it promotes acute myeloid leukemia (AML) by phosphorylating 4EBP1.…”

“…[21][22][23][24] JP11646 has notably been distinguished as the only PIM2 inhibitor exhibiting high selectivity for PIM2 compared with PIM1 and PIM3 and potent activity. [25][26][27] Despite these advances, the present generation of PIM inhibitors confronts considerable challenges. Among these is the concern that they do not significantly alleviate the disease burden or mitigate chemotherapy resistance in patients.…”

“…Among these is the concern that they do not significantly alleviate the disease burden or mitigate chemotherapy resistance in patients. [ 25 ] Furthermore, these inhibitors may trigger off‐target effects at high doses, leading to a range of adverse reactions, such as cardiac events, gastrointestinal issues, febrile neutropenia, and rashes. [ 25 ] This scenario underscores the importance of developing novel scaffold PIM2 inhibitors with high affinity.…”