Proviral Integrations of Moloney Virus (PIM) Kinase Inhibitors as Perspective Chemotherapeutic Agents

Dysfunctional intercellular signaling cascades mediated by oncogenic kinases to maintaintumor cell growth and survival is main characteristic of tumor cells. In normal cells, the activityof these kinases is fine-tuned by different mechanisms, while their prolonged activationpromotes apoptotic resistance and uncontrolled proliferation. PIM kinases are members ofserine/threonine kinase family that their activation is frequently cited in human cancers.Phosphorylation of their downstream substrates activate common pathways controllingvarious physiological processes. PIM kinases activity regulate the balance between cellsurvival and apoptosis. As a result, these kinases represent promising targets for cancertherapy and they are in the center of intense drug development efforts. Understanding howthese kinases control distinct signal transduction pathways is important for designing newdrugs and improving their efficacy in the clinic. The PIM kinases are downstream of multipleoncogenic tyrosine kinase receptors, including Janus kinase (JAK) and FMS-like tyrosinekinase 3 (FLT3). The JAK/STAT pathway has an important role in regulating the expressionof PIM genes. The PIM family consists of three isoforms that are highly conserved throughoutevolution. Since the discovery of PIM kinases, development of PIM inhibitors as perspectiveanticancer drugs has been a priority in both academic and industrial settings. Majority of PIMkinase inhibitors were designed to target the ATP binding pocket of PIM1. Although thePI3K/Akt pathway inhibitors demonstrated acceptable potential in preclinical and clinicaltrials, they could not be used effectively due to acquired resistance. Therefore the PIMkinases represent a promising target for anticancer drug discovery and their frequentoverexpression in cancer and their association with enhanced tumor growth andchemoresistance imply their major role in cancer progression and metastasis. Combination ofPIM inhibitors with PI3K/Akt inhibitors could be an ideal approach to overcome resistancebarrier. A growing body of evidence suggests that PIM kinase inhibitors are much moreeffective when used in combination with other common therapeutic agents for cancer. PIMinhibitors could prevent drug-resistant phenotypes in preclinical models, especially in thecontext of tumor hypoxia. It remain to be determined whether tumor cells will developresistance to PIM kinases inhibitors. The combination of PIM kinases and Akt inhibitorsappears to be a promising option for cancer therapy. Future research on PIM kinases andtheir involvement in mechanisms of drug resistance is needed to recognize the full potentialof PIM inhibitors as a strategy for cancer therapy.

کلیدواژه ها:

PIM Kinases ، Cancer Therapy ، Acquired Resistance ، Hypoxia ، PI3K/Akt Pathway