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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.
AuthorsValentina Piano, Daniel I Benjamin, Sergio Valente, Simone Nenci, Biagina Marrocco, Antonello Mai, Alessandro Aliverti, Daniel K Nomura, Andrea Mattevi
JournalACS chemical biology (ACS Chem Biol) Vol. 10 Issue 11 Pg. 2589-97 (Nov 20 2015) ISSN: 1554-8937 [Electronic] United States
PMID26322624 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Alkyl and Aryl Transferases
  • alkylglycerone-phosphate synthase
Topics
  • Alkyl and Aryl Transferases (antagonists & inhibitors)
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology)
  • Crystallography, X-Ray
  • Drug Discovery
  • Drug Stability
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Small Molecule Libraries (chemistry, pharmacology)
  • Swine
  • Temperature

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