The PIM genes represent a family of proto-oncogenes that encode three different
serine/threonine protein kinases (PIM1, PIM2 and PIM3) with essential roles in the regulation of signal transduction cascades, which promote cell survival, proliferation and drug resistance.
PIM kinases are overexpressed in several hematopoietic
tumors and support in vitro and in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis.
PIM kinases do not have an identified regulatory domain, which means that these
proteins are constitutively active once transcribed. They appear to be critical downstream effectors of important
oncoproteins and, when overexpressed, can mediate drug resistance to available agents, such as
rapamycin. Recent crystallography studies reveal that, unlike other
kinases, they possess a hinge region, which creates a unique binding pocket for
ATP, offering a target for an increasing number of potent small-molecule PIM
kinase inhibitors. Preclinical studies in models of various hematologic
cancers indicate that these novel agents show promising activity and some of them are currently being evaluated in a clinical setting. In this review, we profile the
PIM kinases as targets for
therapeutics in
hematologic malignancies.