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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A.

Authors: Tillotson, Joseph; Kedzior, Magdalena; Guimarães, Larissa; Ross, Alison B; Peters, Tara L; Ambrose, Andrew J; Schmidlin, Cody J; Zhang, Donna D; Costa-Lotufo, Letícia V; Rodríguez, Abimael D; Schatz, Jonathan H; Chapman, Eli

Published In Bioorg Med Chem Lett, (2017 Sep 01)

Abstract: Activation of translation initiation is a common trait of cancer cells. Formation of the heterotrimeric eukaryotic initiation factor F (eIF4F) complex is the rate-limiting step in 5' m7GpppN cap-dependent translation. This trimeric complex includes the eIF4E cap binding protein, the eIF4G scaffolding protein, and the DEAD box RNA helicase eIF4A. eIF4A is an ATP-dependent helicase and because it is the only enzyme in the eIF4F complex, it has been shown to be a potential therapeutic target for a variety of malignancies. To this end, we have used a simple ATPase biochemical screen to survey several hundred marine and terrestrial derived natural products. Herein, we report the discovery of two natural products from marine sources, elisabatin A (1) and allolaurinterol (2), which show low µM inhibition of eIF4A ATPase activity. Enzymological analyses revealed 1 and 2 to be ATP-competitive, and cellular evaluations showed reasonable cytotoxicity against A549 (lung cancer) and MDA-MA-468 (breast cancer) cell lines. However, only compound 2 showed potent inhibition of helicase activity congruent with its ATPase inhibitory activity.

PubMed ID: 28757063 Exiting the NIEHS site

MeSH Terms: Adenosine Triphosphate/metabolism*; Biological Products/chemistry; Biological Products/isolation & purification; Biological Products/pharmacology*; Cell Line, Tumor; Cell Survival/drug effects; Dose-Response Relationship, Drug; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/isolation & purification; Enzyme Inhibitors/pharmacology*; Eukaryotic Initiation Factor-4A/antagonists & inhibitors*; Eukaryotic Initiation Factor-4A/metabolism; Humans; Molecular Structure; Structure-Activity Relationship

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