Research Article: Tricyclic Benzo[cd]azulenes Selectively Inhibit Activities of Pim Kinases and Restrict Growth of Epstein-Barr Virus-Transformed Cells

Date Published: February 6, 2013

Publisher: Public Library of Science

Author(s): Alexandros Kiriazis, Riitta L. Vahakoski, Niina M. Santio, Ralica Arnaudova, Sini K. Eerola, Eeva-Marja Rainio, Ingo B. Aumüller, Jari Yli-Kauhaluoma, Päivi J. Koskinen, Marina Konopleva. http://doi.org/10.1371/journal.pone.0055409

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.

Partial Text

Recently there has been enormous progress in developing small molecule inhibitors against different types of protein kinases, including multiple compounds targeting Pim kinases [1], [2], [3]. The three Pim family members (Pim-1, Pim-2 and Pim-3) form an evolutionary distinct subgroup of serine/threonine-specific kinases that structurally belong to the group of calcium/calmodulin-dependent protein kinases. Pim kinases are highly homologous to each other and have partially overlapping functions and expression patterns [4], [5]. Unlike most other kinases, Pim kinases are constitutively kept in an active conformation [6], which is why their activities correlate well with their expression levels. In hematopoietic cells, expression of Pim kinases is upregulated by numerous growth factors and cytokines such as interleukins [7], [8], [9]. When overexpressed, Pim kinases are oncogenic and have been implicated both in hematopoietic malignancies such as leukemias and lymphomas [10] and in solid tumors such as prostate, colon, oral, hepatic and pancreatic cancers [11], [12].

Pim kinases have recently emerged as promising targets for therapy against both hematological malignancies and solid tumors. Therefore, there is increasing interest towards identification of potent and selective small molecule compounds inhibiting their activity. We have previously described synthesis of tricyclic benzo[cd]azulenes [28], [29], [30] and have now recognized that they possess kinase-inhibitory activity. Moreover, we have observed that under in vitro conditions, some of them show striking selectivity against Pim family kinases as compared with the 68 other protein kinases analysed. They are clearly more effective towards Pim-1 and Pim-3 than Pim-2, which correlates well with observations on several other compounds targeting the Pim family kinases [12], [27]. Since the amino acid sequences as well as structures of Pim family kinases are highly related to each other, their different sensitivities to inhibitory compounds remain to be explained.

Source:

http://doi.org/10.1371/journal.pone.0055409