ATP-competitive,marine derived natural products that target the DEAD box helicase,eIF4A |
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Authors: | 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 |
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Affiliation: | 1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tuscon, AZ 85721, United States;2. Departamento de Farmacologia, Universidade de São Paulo, São Paulo, SP 05508-900, Brazil;3. Sheila and David Fuente Graduate Program in Cancer Biology, Department of Medicine, Division of Hematology-Oncology, 1580 NW 10th Ave, Batchelor, Building, Room 419, M877, Miami, FL 33101, United States;4. Department of Chemistry, University of Puerto Rico, P.O. Box 23346, UPR Station, San Juan, PR 00931-3346, United States |
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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. |
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Keywords: | Cancer Translation eIF4A Natural products DEAD box helicase Inhibitor |
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