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

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

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986710793348554

Publication date: December 1, 2010

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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