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

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

  • Eur J Med Chem. 2019 Feb 1;163:722-735. doi: 10.1016/j.ejmech.2018.11.050.
Giulia Stazi 1,  Cecilia Battistelli 2,  Valentina Piano 3,  Roberta Mazzone 4,  Biagina Marrocco 5,  Sara Marchese 5,  Sharon M Louie 6,  Clemens Zwergel 1,  Lorenzo Antonini 7,  Alexandros Patsilinakos 1,  Rino Ragno 1,  Monica Viviano 8,  Gianluca Sbardella 8,  Alessia Ciogli 1,  Giancarlo Fabrizi 1,  Roberto Cirilli 9,  Raffaele Strippoli 10,  Alessandra Marchetti 2,  Marco Tripodi 11,  Daniel K Nomura 6,  Andrea Mattevi 12,  Antonello Mai 13,  Sergio Valente 14
Affiliations

Affiliations

  • 1 Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.
  • 2 Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
  • 3 Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy; Department of Mechanistic Cell Biology, Max-Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.
  • 4 Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Center for Life Nano Science@Sapienza, Italian Institute of Technology, Via Regina Elena 291, 00161, Rome, Italy.
  • 5 Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.
  • 6 Departments of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, 94720, USA.
  • 7 Alchemical Dynamics s.r.l., 00125, Rome, Italy.
  • 8 Department of Pharmacy, Epigenetic Med Chem Lab, University of Salerno, Via Ponte Don Melillo, 84084, Fisciano, SA, Italy.
  • 9 Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanità, Viale Regina Elena 299, I-00161, Rome, Italy.
  • 10 Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy; Gene Expression Laboratory, National Institute for Infectious Diseases "Lazzaro Spallanzani" I.R.C.C.S., Rome, Italy.
  • 11 Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy; Gene Expression Laboratory, National Institute for Infectious Diseases "Lazzaro Spallanzani" I.R.C.C.S., Rome, Italy; Pasteur Institute - Cenci Bolognetti Foundation, Sapienza Università di Roma, Viale Regina Elena 324, 00161, Rome, Italy.
  • 12 Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy. Electronic address: andrea.mattevi@unipv.it.
  • 13 Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Pasteur Institute - Cenci Bolognetti Foundation, Sapienza Università di Roma, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: antonello.mai@uniroma1.it.
  • 14 Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: sergio.valente@uniroma1.it.
PMID: 30576903 DOI: 10.1016/j.ejmech.2018.11.050
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 1in 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.

Keywords

AGPS inhibitors; Cancer; E-cadherin; Ether lipids; Snail.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153910
    99.74%, AGPS Binder