Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents
| Autor: | Daniel I. Benjamin, Alessandro Aliverti, Antonello Mai, Sergio Valente, Biagina Marrocco, Daniel K. Nomura, Andrea Mattevi, Simone Nenci, Valentina Piano |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular binding Swine Antineoplastic Agents Ether antimycin glycerol Crystallography X-Ray dihydroxyacetone phosphate Biochemistry Article Small Molecule Libraries chemistry.chemical_compound Drug Stability Drug Discovery Animals Humans Enzyme Inhibitors chemistry.chemical_classification Alkyl and Aryl Transferases Molecular Structure ATP synthase biology Eicosanoid metabolism Chemistry Drug discovery Temperature General Medicine stability cancer pathogenicity biochemistry molecular medicine guinea-pig liver alkyl biosynthesis metabolism 3. Good health Enzyme Ether lipid Cancer cell Glycerophospholipid biology.protein Molecular Medicine lipids (amino acids peptides and proteins) |
| Zdroj: | ACS Chemical Biology. 10:2589-2597 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.5b00466 |
| Popis: | Dysregulated ether lipid metabolism is an important hallmark of cancer cells. Previous studies have reported that lowering ether lipid levels by genetic ablation of the ether lipid-generating enzyme alkyl-glycerone phosphate synthase (AGPS) lowers key structural and oncogenic ether lipid levels and alters fatty acid, glycerophospholipid, and eicosanoid metabolism to impair cancer pathogenicity, indicating that AGPS may be a potential therapeutic target for cancer. In this study, we have performed a small-molecule screen to identify candidate AGPS inhibitors. We have identified several lead AGPS inhibitors and have structurally characterized their interactions with the enzyme and show that these inhibitors bind to distinct portions of the active site. We further show that the lead AGPS inhibitor 1a selectively lowers ether lipid levels in several types of human cancer cells and impairs their cellular survival and migration. We provide here the first report of in situ-effective pharmacological tools for inhibiting AGPS, which may provide chemical scaffolds for future AGPS inhibitor development for cancer therapy. |
| Databáze: | OpenAIRE |
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