EIF4E公司
激酶
癌症研究
PI3K/AKT/mTOR通路
癌变
癌症
MAPK/ERK通路
生物
细胞生物学
信号转导
翻译(生物学)
信使核糖核酸
基因
生物化学
遗传学
作者
Susann Santag,Franziska Siegel,Antje M. Wengner,Claudia Lange,Ulf Bömer,Knut Eis,Florian Pühler,Philip Lienau,Linda Bergemann,Martin Michels,Franz von Nussbaum,Dominik Mumberg,Kirstin Petersen
标识
DOI:10.1016/j.canlet.2016.12.029
摘要
The initiation of mRNA translation has received increasing attention as an attractive target for cancer treatment in the recent years. The oncogenic eukaryotic translation initiation factor 4E (eIF4E) is the major substrate of MAP kinase-interacting kinase 1 (MNK1), and it is located at the junction of the cancer-associated PI3K and MAPK pathways. The fact that MNK1 is linked to cell transformation and tumorigenesis renders the kinase a promising target for cancer therapy. We identified a novel small molecule MNK1 inhibitor, BAY 1143269, by high-throughput screening and lead optimization. In kinase assays, BAY 1143269 showed potent and selective inhibition of MNK1. By targeting MNK1 activity, BAY 1143269 strongly regulated downstream factors involved in cell cycle regulation, apoptosis, immune response and epithelial–mesenchymal transition in vitro or in vivo. In addition, BAY 1143269 demonstrated strong efficacy in monotherapy in cell line and patient-derived non-small cell lung cancer xenograft models as well as delayed tumor regrowth in combination treatment with standard of care chemotherapeutics. In summary, the inhibition of MNK1 activity with a highly potent and selective inhibitor BAY 1143269 may provide an innovative approach for anti-cancer therapy.
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