Sensitizing triple negative breast cancer to approved therapies: Design, synthesis and biological activity of MNK inhibitors


Bou Petit, Elisabeth  


Deregulation of protein synthesis is a common event in cancer. A key player in translational control is eIF4E whose function is modulated by the MAP kinase interacting kinases 1 and 2 (MNK1/2) through phosphorylation of a conserved serine (Ser209). In the recent years, eIF4E has been described as an independent prognostic factor associated with malignant progression and development of resistance. Moreover, eIF4E is found to be overexpressed in ovarian, breast, lung, colon, bladder and prostate cancer. eIF4E phosphorylation is necessary for oncogenic transformation while dispensable for normal development. Hence, pharmacologic MNK inhibitors may provide a non-toxic and effective anti-cancer strategy, especially in combination with approved treatments. In this project, the pyrazolo[3,4-b]pyridinic systems have been proposed as potential candidates as MNK inhibitors due to their similarity with known effective inhibitors. During this project, the synthetic possibilities offered by these scaffolds have been deeply studied defining general methodologies to achieve selective and controlled substitutions in 6 different points of the central core. Moreover, the reaction mechanisms have been described. Up to 5 families of compounds based on the pyrazolo[3,4-b]pyridine scaffold were studied and one of the families showed interesting activity on the preliminary assays. Three compounds (EB1-3), with IC50 values in the low μM range (0.7 to 4 μM), showed a complete and selective inhibition of MNKs (between 2.5 and 5 μM) and no significant cell toxicity in the triple negative breast cancer cell line MDA-MB-231. Moreover, co-treatment with EB1 clearly increased the sensitivity of MDA-MB 231 cells to doxorubicin improving the efficacy of the drug in inhibiting cell growth. A structure-based drug design strategy was applied to understand the mechanism of interaction of the different candidates. Models of the active/inactive forms of MNK1 were created and used to predict the binding mode of the hits. EB1 seems to be a type II inhibitor which selectively binds to the inactive form of MNK1 and interacts with the DFD (Asp-Phe-Asp) motif, a unique feature of MNKs. 


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Borrell Bilbao, Jose Ignacio  
Ramon y Cajal Agüeras, Santiago  
Estrada Tejedor, Roger  


IQS SE - Química Orgànica i Farmacèutica

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