European Journal of Medicinal Chemistry p. 722 - 735 (2019)
Update date:2022-08-03
Topics:
Stazi, Giulia
Battistelli, Cecilia
Piano, Valentina
Mazzone, Roberta
Marrocco, Biagina
Marchese, Sara
Louie, Sharon M.
Zwergel, Clemens
Antonini, Lorenzo
Patsilinakos, Alexandros
Ragno, Rino
Viviano, Monica
Sbardella, Gianluca
Ciogli, Alessia
Fabrizi, Giancarlo
Cirilli, Roberto
Strippoli, Raffaele
Marchetti, Alessandra
Tripodi, Marco
Nomura, Daniel K.
Mattevi, Andrea
Mai, Antonello
Valente, Sergio
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.
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