This Article Full Text (PDF) Brault et al. Supplementary Appendix Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Brault, L. Articles by Schwaller, J. PubMed PubMed Citation Articles by Brault, L. Articles by Schwaller, J.

PIM serine/threonine kinases in pathogenesis and therapy of hematological malignancies and solid cancers

¹ University Hospital Basel, Department of Biomedicine, Basel, Switzerland
² Ludwig-Maximilians-Universität, Department of Pharmacy, Munich, Germany
³ Oxford University, Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Old Road Campus Building, Oxford OX3 7DQ, United Kingdom

*Correspondence to: Jürg Schwaller M.D., Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland Phone: + 41 61 265 35 04 Fax: + 41 61 265 23 50 E-mail: j.schwaller{at}unibas.ch

ABSTRACT

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 haematological malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumours. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumour 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 haematopoietic 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 hematological 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.

Key words: PIM kinases, leukemia, solid cancer, structure, small molecule inhibitors.