Fighting Tumor Cell Survival: Advances in the Design and Evaluation of Pim Inhibitors

F.      Anizon; A.      A. Shtil; V.      N. Danilenko; P.      Moreau

Abstract

The Pim (provirus insertion site of Moloney murine leukemia virus) family of serine/threonine protein kinases possesses the fundamental characteristics critical for the biology of eukaryotes, in particular, survival and malignant transformation of cells. The members of this protein family (Pim-1 to Pim-3) are aberrantly expressed in human tumors, most frequently in prostate cancer and hematological malignancies. Therefore, Pim proteins are widely considered as attractive targets in cancer chemotherapy. Growing knowledge of mechanisms of Pim-mediated anti-apoptosis and transformation, as well as rapid progress in the design of Pim-modulating compounds dictate the need for an in-depth analysis of the chemistry of inhibitors and the modes of their interaction with these protein kinases. This review summarizes recent advances in understanding the molecular events regulated by Pim proteins. In addition, we focus on the non-patent literature (mostly since 2005) that demonstrates a diversity of chemical classes of small molecular weight Pim inhibitors. The X-ray co-crystal structures of complexes Pim:inhibitor provide evidence for SAR data important for the choice of synthetic routes, optimization of lead compounds and testing chemical libraries. We also discuss a cell-based test system useful for rapid and inexpensive pre-screening of compounds capable of preventing Pim-mediated phosphorylation.

Keywords: Cancer, Pim family, serine/threonine protein kinases, small molecular weight inhibitors, test systems, Fighting Tumor Cell Survival, Pim Inhibitors, EMPHASIS, Moloney leukemia provirus, Phosphorylation, malignant transformation, promotes mitochondrial integrity, mitochondrial fraction, overexpression, transcriptional activity, pro-apoptotic protein, chemotherapeutic, AMP-PNP, hydrogen-bonding network, protein kinases, Quercetagetin 7, Myricetin 4, Staurosporine, Adenosine, carbonitrile, cyclin-dependent kinase, fisetin 2, 3 Kaempferol, Lys67, Glu89, Indolocarbazole, bisindolylmaleimide, ruthenium complex, Bim-8, cyclopentadienyl, ATP-binding site, hydrophobic interactions, ruthenium stereogenic center, pyrrazolo, antileukemic activity, cytotoxic effect, re-sensitized, triazolo, low nanomolar, isoxazole nitrogen, benzothienopyrimidinone, 5-Benzylidenethiazolidine-2, pharmakokinetic profile, Kenpaullone, Isogranulatimide, submicromolar, aromatic, highly enhanced, Dyrk1A, c-Jun N-terminal kinase, DMAT, SB 216763, ATP-binding pocket, tentative Pim modulators, inconsistent, high throughput screening, aminoglycoside, Streptomyces coelicolor, kanamycin, phenomenon regulated, Escherichia coli possess, cell-free systems, antitumor drug targets, chemotherapeutic drug(s), implicates