ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A
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Author
Tillotson, JosephKedzior, 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
Affiliation
Univ Arizona, Coll Pharm, Dept Pharmacol & ToxicolIssue Date
2017-09-01
Metadata
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PERGAMON-ELSEVIER SCIENCE LTDCitation
Tillotson, 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 reservedCollection Information
This 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 repository@u.library.arizona.edu.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 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.Note
24 month embargo; available online 19 July 2017.ISSN
0960894XVersion
Final accepted manuscriptSponsors
University of Arizona; National Institutes of Health (NIH) Training Grant [T32 GM008804, T32 HL007249]; National Institute of Environmental Health Sciences Training Grant [T32 ES007091]Additional Links
https://linkinghub.elsevier.com/retrieve/pii/S0960894X17307412ae974a485f413a2113503eed53cd6c53
10.1016/j.bmcl.2017.07.045