Piano Valentina, Benjamin Daniel I, Valente Sergio, Nenci Simone, Marrocco Biagina, Mai Antonello, Aliverti Alessandro, Nomura Daniel K, Mattevi Andrea
Department of Biology and Biotechnology, University of Pavia , via Ferrata 9, 27100 Pavia, Italy.
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley , Berkeley, California 94720, United States.
ACS Chem Biol. 2015 Nov 20;10(11):2589-97. doi: 10.1021/acschembio.5b00466. Epub 2015 Sep 4.
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.
醚脂代谢失调是癌细胞的一个重要特征。先前的研究报道，通过对生成醚脂的酶——烷基甘油磷酸合酶（AGPS）进行基因敲除来降低醚脂水平，可降低关键的结构醚脂和致癌醚脂水平，并改变脂肪酸、甘油磷脂和类花生酸代谢，从而损害癌症致病性，这表明AGPS可能是癌症的一个潜在治疗靶点。在本研究中，我们进行了小分子筛选以鉴定候选AGPS抑制剂。我们已经鉴定出几种先导AGPS抑制剂，并对它们与该酶的相互作用进行了结构表征，结果表明这些抑制剂与活性位点的不同部分结合。我们进一步表明，先导AGPS抑制剂1a可选择性降低几种类型人类癌细胞中的醚脂水平，并损害其细胞存活和迁移能力。我们在此首次报道了用于抑制AGPS的原位活性药理学工具，这可能为未来开发用于癌症治疗的AGPS抑制剂提供化学支架。
