Family of the oncogenic PIM kinases: potential targets in lymphoid and myeloid malignancies

Abstract

The PIM family of serine-threonine kinases comprises three homologous proteins, PIM1, PIM2 and PIM3, regulating a broad spectrum of cellular substrates. They also tune important processes such as translation, transcription, proliferation, apoptosis, metabolism and migration. In addition, PIM kinases augment and consolidate the oncogenic potential of certain strong oncogenes, such as c-MYC and BCL6. PIM kinases play an important pathogenetic role in multiple haematological and solid malignancies, and in some tumours their expression is associated with adverse prognosis. PIM kinases do not require post-translational modifications for their activity. Mild phenotypes of triple 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 design of specific small molecule inhibitors. 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 a 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.