ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A
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.
AffiliationUniv Arizona, Coll Pharm, Dept Pharmacol & Toxicol
MetadataShow full item record
PublisherPERGAMON-ELSEVIER SCIENCE LTD
CitationTillotson, J., Kedzior, M., Guimarães, L., Ross, A. B., Peters, T. L., Ambrose, A. J., ... & Schatz, J. H. (2017). ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A. Bioorganic & medicinal chemistry letters, 27(17), 4082-4085.
Rights© 2017 Elsevier Ltd. All rights reserved
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractActivation 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 mu M 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. (C) 2017 Elsevier Ltd. All rights reserved.
Note24 month embargo; available online 19 July 2017.
VersionFinal accepted manuscript
SponsorsUniversity of Arizona; National Institutes of Health (NIH) Training Grant [T32 GM008804, T32 HL007249]; National Institute of Environmental Health Sciences Training Grant [T32 ES007091]