Development of alkyl glycerone phosphate synthase inhibitors: Structure-activity relationship and effects on ether lipids and epithelial-mesenchymal transition in cancer cells

Giulia Stazi, Cecilia Battistelli, Valentina Piano, Roberta Mazzone, Biagina Marrocco, Sara Marchese, Sharon M. Louie, Clemens Zwergel, Lorenzo Antonini, Alexandros Patsilinakos, Rino Ragno, Monica Viviano, Gianluca Sbardella, Alessia Ciogli, Giancarlo Fabrizi, Roberto Cirilli, Raffaele Strippoli, Alessandra Marchetti, Marco Tripodi, Daniel K. NomuraAndrea Mattevi, Antonello Mai, Sergio Valente

Research output: Contribution to journalArticlepeer-review

Abstract

In aggressive tumors, alkylglyceronephosphate synthase (AGPS) controls cellular ether phospholipid utilization and metabolism to promote cancer cell proliferation and motility. SAR studies on the first-in-class AGPS inhibitor 1, discovered by our group, led to the 2,6-difluoro analog 2i which showed higher binding affinity than 1 in vitro. In 231MFP cancer cells, 2i reduced ether lipids levels and cell migration rate. When tested in PC-3 and MDA-MB-231 cancer cells, 2i specifically impaired epithelial to mesenchymal transition (EMT) by modulating E-cadherin, Snail and MMP2 expression levels. Moreover, the combination of siRNAs against AGPS and 2i provided no additive effect, confirming that the modulation of 2i on EMT specifically relies on AGPS inhibition. Finally, this compound also affected cancer cell proliferation especially in MDA-MB-231 cells expressing higher AGPS level, whereas it provided negligible effects on MeT5A, a non-tumorigenic cell line, thus showing cancer specificity.

Original languageEnglish
Pages (from-to)722-735
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume163
DOIs
Publication statusPublished - Feb 1 2019

Keywords

  • AGPS inhibitors
  • Cancer
  • E-cadherin
  • Ether lipids
  • Snail

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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