Abstract A49: Repression of tumor survival pathways by novel, selective inhibitors of MNK1 and MNK2 kinases

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 19_Supplement; p. A49
• Main Authors: Rzymski, Tomasz, Dreas, Agnieszka, Milik, Mariusz, Kucwaj, Katarzyna, Zarebski, Adrian, Skuta, Malgorzata Szajewska, Cierpich, Anna, Fabritius, Charles, Brzozka, Krzysztof
• Format: Journal Article
• Language: English
• Published: 01.10.2013
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.FBCR13-A49

Abstract MNK1 and MNK2 are MAP kinase-interacting kinases involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4E on a conserved serine 209. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, mice that lack both MNK1 and MNK2 do not have any apparent phenotype and therefore represent interesting possibility to develop targeted and safe anticancer therapies. Herewith, we report the development of first selective small molecule inhibitors of MNK1 and MNK2 kinases and their in vitro cellular activity. Selvita developed a series of small molecule type I, ATP-competitive inhibitors targeting both MNK1 and MNK2 with mid nM activity range. Selected compounds were tested on a panel of 456 kinases and showed very high selectivity. Additionally, in cellular models such as serum stimulated SW480 cells, synthesized MNK1/2 inhibitors caused dose dependent inhibition of phosphorylation of eIF4e at Ser209 in line with the kinase activity profile. The observed cellular activity on biomarker inhibition was more potent than observed for reported in the literature MNK1/2 inhibitors such as cercosporamide and CGP57380. High activity of MNK1/2 inhibitors on in vitro biomarkers correlated with efficacy on cancer cells challenged with various stress conditions, typical for tumor microenvironment. These initial findings confirm that selective inhibition of MNK1/2 may repress major tumor survival pathways induced under stress and support further development of this class of compounds as a novel anticancer therapy with a promising therapeutic window. Citation Format: Tomasz Rzymski, Agnieszka Dreas, Mariusz Milik, Katarzyna Kucwaj, Adrian Zarebski, Malgorzata Szajewska Skuta, Anna Cierpich, Charles Fabritius, Krzysztof Brzozka. Repression of tumor survival pathways by novel, selective inhibitors of MNK1 and MNK2 kinases. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A49.