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
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tuscon, AZ 85721, United States.
Departamento de Farmacologia, Universidade de São Paulo, São Paulo, SP 05508-900, Brazil.
Bioorg Med Chem Lett. 2017 Sep 1;27(17):4082-4085. doi: 10.1016/j.bmcl.2017.07.045. Epub 2017 Jul 19.
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.
翻译起始的激活是癌细胞的一个共同特征。异源三聚体真核起始因子F（eIF4F）复合物的形成是5' m7GpppN帽依赖性翻译中的限速步骤。这个三聚体复合物包括eIF4E帽结合蛋白、eIF4G支架蛋白和DEAD盒RNA解旋酶eIF4A。eIF4A是一种ATP依赖性解旋酶，由于它是eIF4F复合物中唯一的酶，已被证明是多种恶性肿瘤的潜在治疗靶点。为此，我们使用了一种简单的ATP酶生化筛选方法来检测数百种海洋和陆地来源的天然产物。在此，我们报告从海洋来源发现了两种天然产物，elisabatin A（1）和别劳因特尔醇（2），它们对eIF4A ATP酶活性表现出低 microM抑制作用。酶学分析表明1和2是ATP竞争性的，细胞评估显示它们对A549（肺癌）和MDA-MA-−468（乳腺癌）细胞系具有合理的细胞毒性。然而，只有化合物2表现出与其ATP酶抑制活性一致的对解旋酶活性的有效抑制作用。
