Discovery of Mitogen-Activated Protein Kinase-Interacting Kinase 1 Inhibitors by a Comprehensive Fragment-Oriented Virtual Screening Approach

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• 作者：Julen Oyarzabal ; Natasha Zarich ; Mara Isabel Albarran ; Irene Palacios ; Manuel Urbano-Cuadrado ; Genoveva Mateos ; Isabel Reymundo ; Obdulia Rabal ; Antonio Salgado ; Ana Corrionero ; Jess Fominaya ; Joaquin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：September 23, 2010
• 年：2010
• 卷：53
• 期：18
• 页码：6618-6628
• 全文大小：1047K
• 年卷期：v.53,no.18(September 23, 2010)
• ISSN：1520-4804

文摘

Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate the oncogene eIF4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. To investigate if pharmacological inhibition of MNK1 could be useful for the treatment of cancers, we pursued a comprehensive virtual screening approach to rapidly identify pharmacological tools for target validation and to find optimal starting points for a plausible medicinal chemistry project. A collection of 1236 compounds, selected from a library of 42168 compounds and a database of 18.8 million structures, were assayed. Of the identified hits, 26 were found to have IC₅₀ values less than 10 μM (2.10% hit rate). The most potent compound had an IC₅₀ value of 117 nM, and 73.1% of these hits were fragments. The hits were characterized by a high ligand efficiency (0.32−0.52 kcal/mol per heavy atom). Ten different chemical scaffolds were represented, giving a chemotype/hit ratio of 0.38.