The quest for novel anticancer drugs has led to a vast number of tumor inhibitory compounds from various natural sources including plants, animals, microbes, and marine organisms. One recently discovered antitumor natural product of marine origin is the structurally unique brominated oroidin alkaloid (-)-agelastatin A (AglA), derived fro the marine sponge Agelas dendromorpha [1]. The goal of this project is to elucidate a molecular target of AglA. In the current realm of drug discovery, there is no single method satisfactory for identifying protein targets of bioactive small molecules. By using both a top-down and bottom up approach, I expect to elucidate a target of the novel natural product AglA [2]. Based on preliminary data, I hypothesize that the site of action of AglA is a post-initiation stage of translation.
Aim 1 serves to narrow down the site of perturbation and elucidate a molecular target by taking advantage of cellular and in vitro assays specific to eukaryotic protein translation.
Aim 2 serves to identify a molecular target through direct chemical modification of AglA. This is significant because protein synthesis plays a huge role in cell survival, especially n fast-proliferating cancer cells. Several inhibitors of eukaryotic protein synthesis, including the translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate), have entered the clinical stage, establishing translation as a promising target for chemotherapy [3]. Not only i this promising for future cancer therapeutics; perturbation of translation will allow us to dissect minute molecular details of the process, providing valuable insight into the eukaryotic ribosome and its components.
Protein translation plays an essential role in cell proliferation and survival. Fast proliferating cancer cells are especially dependent on protein synthesis. Identifying the mechanism of agelastatin A and other inhibitors of eukaryotic translation will not only allow dissection of sophisticated eukaryotic translation machinery for general scientific knowledge, but also provide hope for promising new anticancer drugs.
| McClary, Brandon; Zinshteyn, Boris; Meyer, Mélanie et al. (2017) Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A. Cell Chem Biol 24:605-613.e5 |
| Jouanneau, Morgan; McClary, Brandon; Reyes, Jeremy Chris P et al. (2016) Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe. Bioorg Med Chem Lett 26:2092-7 |
