Tricyclic Benzo[cd]azulenes selectively inhibit activities of Pim kinases and restrict growth of Epstein-Barr virus-transformed cells

PLoS One. 2013;8(2):e55409. doi: 10.1371/journal.pone.0055409. Epub 2013 Feb 6.

Abstract

Oncogenic Pim family kinases are often overexpressed in human hematopoietic malignancies as well as in solid tumours. These kinases contribute to tumorigenesis by promoting cell survival and by enhancing resistance against chemotherapy and radiation therapy. Furthermore, we have recently shown that they increase the metastatic potential of adherent cancer cells. Here we describe identification of tricyclic benzo[cd]azulenes and their derivatives as effective and selective inhibitors of Pim kinases. These compounds inhibit Pim autophosphorylation and abrogate the anti-apoptotic effects of Pim kinases. They also reduce cancer cell motility and suppress proliferation of lymphoblastoid cell lines infected and immortalized by the Epstein-Barr virus. Thus, these novel Pim-selective inhibitors provide promising compounds for both research and therapeutic purposes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Azulenes / pharmacology*
  • Carcinogenesis / drug effects
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Transformation, Viral / drug effects*
  • Herpesvirus 4, Human / drug effects*
  • Herpesvirus 4, Human / metabolism
  • Humans
  • Mice
  • Myeloid Cells / drug effects*
  • Myeloid Cells / virology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-pim-1 / metabolism

Substances

  • Azulenes
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim

Grant support

LSHB-CT-2004-503467 to J.Y.K.), the Academy of Finland (grant 108376 to J.Y.K), Graduate School in Pharmaceutical Research (A.K.) and Walter och Lisi Wahls Stiftelse för Naturvetenskaplig Forskning (J.Y.K.). The biological experiments were supported by the Academy of Finland (grants 111820 and 121533 to P.J.K.), the Drug Discovery Graduate School (R.L.V., N.M.S.), Turku University Foundation (N.M.S.), the Orion-Farmos Research Foundation (R.L.V.), the Cancer Society of Finland (R.L.V.), the Maud Kuistila Foundation (R.L.V.) and the CIMO exchange programme (R.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.