title: LXY6090 - a novel manassantin A derivative - limits breast cancer growth through hypoxia-inducible factor-1 inhibition.
abstract: 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-1α, 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-1α 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.
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Lai
authors.affiliation: Department of Pharmacology, National Institutes for Food and Drug Control.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pharmacochemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College.
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Pharmacochemistry, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Chen
keywords: LXY6090; antitumor; breast cancer; hypoxia-inducible factor-1; manassantin A derivative