期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 17, 页码 4082-4085出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.07.045
关键词
Cancer; Translation; eIF4A; Natural products; DEAD box helicase; Inhibitor
资金
- University of Arizona
- National Institutes of Health (NIH) Training Grant [T32 GM008804, T32 HL007249]
- National Institute of Environmental Health Sciences Training Grant [T32 ES007091]
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.
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