Journal
ONCOTARGETS AND THERAPY
Volume 9, Issue -, Pages -Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S106925
Keywords
hypoxia-inducible factor-1; manassantin A derivative; antitumor; breast cancer; LXY6090
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Funding
- Beijing Natural Science Foundation [7121010]
- National Science and Technology Major Project [2012ZX09301002-006]
- National Natural Science Foundation of China [81301916]
- Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study [BZ0150]
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Hypoxia-inducible factor-1 (HIF-1) represents a novel antitumor target owing to its involvement in vital processes considered hallmarks of cancer phenotypes. Manassantin A (MA) derived from Saururus cernuus has been reported as a selective HIF-1 inhibitor. Herein, the structure of MA was optimized to achieve new derivatives with simple chemical properties while retaining its activity. LXY6090 was designed to replace the central tetrahydrofuran moiety of MA with a cyclopentane ring and was identified as a potent HIF-1 inhibitor with an IC50 value of 4.11 nM. It not only inhibited the activity of HIF-1 in breast cancer cells but also downregulated the protein level of HIF-1 alpha, which depended on von Hippel-Lindau for proteasome degradation. The related biological evaluation showed that the activity of HIF-1 target genes, VEGF and IGF-2, was decreased by LXY6090 in breast cancer cell lines. LXY6090 presented potent antitumor activity in vitro. Furthermore, LXY6090 showed in vivo anticancer efficacy by decreasing the HIF-1 alpha expression in nude mice bearing MX-1 tumor xenografts. In conclusion, our data provide a basis for the future development of the novel compound LXY6090 as a potential therapeutic agent for breast cancer.
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