Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents

ACS Chemical Biology
Valentina PianoAndrea Mattevi

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.

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Citations

Nov 12, 2016·Biochemical and Biophysical Research Communications·Valentina PianoAndrea Mattevi
Jun 28, 2017·Archives of Biochemistry and Biophysics·Pablo Sobrado, John J Tanner
Mar 9, 2018·Lipids in Health and Disease·Márcia Cristina Fernandes MessiasPatrícia de Oliveira Carvalho
Sep 17, 2018·Histochemistry and Cell Biology·Markus IslingerMichael Schrader
Jul 18, 2020·Cells·Jung-Ae Kim
Sep 18, 2020·Nature·Yilong ZouStuart L Schreiber
Jul 4, 2018·Biogerontology·Nayan M DeoriShirisha Nagotu
May 20, 2017·Protein & Cell·John M Dean, Irfan J Lodhi
Jan 6, 2021·Neurotoxicity Research·Rachayeeta DebShirisha Nagotu
Mar 12, 2021·Free Radical Biology & Medicine·Guanghan FanXiao Xu
Mar 10, 2017·Trends in Biochemical Sciences·Valentina PianoAndrea Mattevi
Apr 17, 2021·Nature Genetics·Michael WainbergAnshul Kundaje
May 15, 2021·Trends in Endocrinology and Metabolism : TEM·Maceler AldrovandiMarcus Conrad
Jun 3, 2021·Cells·Caroline FischerIrmgard Tegeder
Jun 26, 2018·Chemical Reviews·Jessica L CounihanDaniel K Nomura
Jul 12, 2020·Developmental Cell·Marcos A PerezJennifer L Watts
May 30, 2019·ACS Central Science·Netta VidavskyLara A Estroff
Oct 1, 2021·The Protein Journal·Preantha PoonanMahmoud E S Soliman

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