PIM kinases as therapeutic targets in lymphoid and myeloid malignancies

Abstract

PIM family of serine-threonine kinases comprises three homologous proteins, PIM1, PIM2 and PIM3, regulating broad spectrum of cellular substrates and tuning important processes, such as translation, transcription, proliferation, apoptosis, metabolism and migration. In addition, PIM kinases cooperate with, augment and consolidate the transforming potential of other strong oncogenes, such as c-MYC and BCL6. PIM kinases play important pathogenetic role in multiple hematologic and solid malignancies, and in some tumors their expression is associated with adverse prognosis. PIM kinases do not require posttranslational modifications for their activity. Mild phenotypes of knockout mice, lacking all PIM isoforms suggest that PIM kinases are good, druggable targets and their pharmacological inhibition will be well tolerated. The unique structure-function relationship facilitates designing specific small molecule inhibitors, and multiple such compounds targeting PIM kinases have been identified. PIM inhibitors exhibit promising activity against in vitro and in vivo models of multiple lymphoid and myeloid malignancies. However, given the unique mechanism of PIM kinases regulation, definition of pathogenetically important level of PIM expression is not feasible, and rational, clinically useful biomarker has not been yet developed. Identification of such biologically and clinically relevant biomarkers is the major challenge hampering successful translation of basic knowledge on PIM biology to clinically available drugs.