Abstract 755: Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in glioblastoma and colorectal cancer

Herewith, we report development of small molecule inhibitors of MNK1 and MNK2 kinases and their cellular activity. MNK1 and 2 are MAP kinase-interacting kinases that are activated by RAS and MAPK signaling pathways and are involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4e on a conserved serine 209 residue. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in various tumor types. Interestingly, mice that lack both MNK1 and MNK2 do not have any apparent phenotype, which is promising for the therapeutic window of MNK1/2 inhibitors. SEL201 is a series of small molecule inhibitors which inhibit activity of both MNK1 and MNK2 in a low nM range. Selected compounds were tested on the kinome panels and indicated MNK1 and MNK2 as primary kinase targets. SEL201 compounds caused dose dependent inhibition of phosphorylation of eIF4e at Ser209 in various cancer cell lines at concentrations Citation Format: Tomasz Rzymski, Malgorzata Szajewska-Skuta, Adrian Zarebski, Kamil Sitarz, Lukasz Sapala, Malgorzata Zurawska, Magdalena Salwinska, Renata Windak, Ewa Trebacz, Joanna Daniel-Wojcik, Radoslaw Obuchowicz, Bozena Winnik, Ewelina Wincza, Urszula Kulesza, Katarzyna Kucwaj-Borysz, Mariusz Milik, Agnieszka Dreas, Krzysztof Brzozka. Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in glioblastoma and colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 755. doi:10.1158/1538-7445.AM2014-755