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: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages4082-4085
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number17
DOIs
StatePublished - 2017
Externally publishedYes

Fingerprint

Biological Products
Adenosine Triphosphatases
Adenosine Triphosphate
Neoplasms
Cells
DEAD-box RNA Helicases
RNA Cap-Binding Proteins
Eukaryotic Initiation Factors
Lung Neoplasms
Breast Neoplasms
Cell Line
Enzymes
Proteins
Therapeutics
Surveys and Questionnaires
elisabatin A
Cytotoxicity
Chemical activation

Keywords

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

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., ... 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. DOI: 10.1016/j.bmcl.2017.07.045

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

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 17, 2017, p. 4082-4085.

Research output: Research - peer-reviewArticle

Tillotson, J, Kedzior, M, Guimarães, L, Ross, AB, Peters, TL, Ambrose, AJ, Schmidlin, CJ, Zhang, DD, Costa-Lotufo, LV, Rodríguez, AD, Schatz, JH & Chapman, E 2017, 'ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A' Bioorganic and Medicinal Chemistry Letters, vol 27, no. 17, pp. 4082-4085. DOI: 10.1016/j.bmcl.2017.07.045
Tillotson J, Kedzior M, Guimarães L, Ross AB, Peters TL, Ambrose AJ et al. ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A. Bioorganic and Medicinal Chemistry Letters. 2017;27(17):4082-4085. Available from, DOI: 10.1016/j.bmcl.2017.07.045
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. / ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A. In: Bioorganic and Medicinal Chemistry Letters. 2017 ; Vol. 27, No. 17. pp. 4082-4085
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