title: Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents.
abstract: 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-active pharmacological tools for inhibiting AGPS, which may provide chemical scaffolds for future AGPS inhibitor development for cancer therapy.
authors: Department of Biology and Biotechnology, University of Pavia , via Ferrata 9, 27100 Pavia, Italy.
authors: Valentina
authors: V
authors: Piano
authors: Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors: Daniel I
authors: DI
authors: Benjamin
authors: Department of Drug Chemistry and Technologies, University "La Sapienza" , P. le A. Moro 5, Roma 00185, Italy.
authors: Sergio
authors: S
authors: Valente
authors: Department of Biology and Biotechnology, University of Pavia , via Ferrata 9, 27100 Pavia, Italy.
authors: Simone
authors: S
authors: Nenci
authors: Department of Drug Chemistry and Technologies, University "La Sapienza" , P. le A. Moro 5, Roma 00185, Italy.
authors: Biagina
authors: B
authors: Marrocco
authors: Department of Drug Chemistry and Technologies, University "La Sapienza" , P. le A. Moro 5, Roma 00185, Italy.|Pasteur Institute, Cenci Bolognetti Foundation , P.le A. Moro 5, Roma 00185, Italy.
authors: Antonello
authors: A
authors: Mai
authors: Department of Biosciences, University of Milano , Via Festa del Perdono, 7, 20122 Milano, Italy.
authors: Alessandro
authors: A
authors: Aliverti
authors: Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
authors: Daniel K
authors: DK
authors: Nomura
authors: Department of Biology and Biotechnology, University of Pavia , via Ferrata 9, 27100 Pavia, Italy.
authors: Andrea
authors: A
authors: Mattevi
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013552:Swine; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase