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

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

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4082-4085
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number17
DOIs
StatePublished - Jan 1 2017

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Keywords

  • Cancer
  • DEAD box helicase
  • Inhibitor
  • Natural products
  • Translation
  • eIF4A

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Tillotson, J., Kedzior, M., Guimarães, L., Ross, A. B., Peters, T. L., Ambrose, A. J., Schmidlin, C. J., Zhang, D. D., Costa-Lotufo, L. V., Rodríguez, A. D., Schatz, J. H., & Chapman, E. (2017). ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A. Bioorganic and Medicinal Chemistry Letters, 27(17), 4082-4085. https://doi.org/10.1016/j.bmcl.2017.07.045