The identification as cooperating targets of Proviral Integrations of Moloney virus in murine
lymphomas suggested early on that PIM
serine/threonine kinases play an important role in
cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in
hematologic malignancies and
prostate cancer, increased PIM3 expression was observed in different solid
tumors.
PIM kinases are constitutively active and their activity supports in vitro and in vivo
tumor cell growth and survival through modification of an increasing number of common as well as
isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating
chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that
PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the
protein structure facilitated identification of an increasing number of potent small molecule PIM
kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify
isoform-specific PIM inhibitors that would not only help to dissect the
kinase function but hopefully also provide targeted
therapeutics. Here, we summarize the current knowledge about the role of PIM
serine/threonine kinases for the pathogenesis and
therapy of
hematologic malignancies and solid
cancers, and we highlight structural principles and recent progress on small molecule PIM
kinase inhibitors that are on their way into first clinical trials.