title: Synthesis and biological evaluation of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors.
abstract: Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is recognized as an attractive therapeutic target in multiple malignancies. In this study, a series of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides were synthesized and biologically evaluated for their potential LSD1 inhibitory effect. Among them, compounds 5a and 5n showed the most potent LSD1 inhibitory activity with IC50 values of 1.4 and 1.7nM, respectively, which were about 10 times more potent compared with (E)-N-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-(morpholinosulf-only) benzohydrazide (J. Med. Chem.2013, 56, 9496-9508; as reference compound). Compounds 5a and 5n also exhibited marked anti-proliferation activities against cancer cell lines that highly expressed LSD1. These results suggest that these optimized compounds might be served as promising LSD1 inhibitors against cancer, which merit further study.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Xin-Mei
authors.initials: XM
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medicinal School, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: zhaoyinglan@scu.edu.cn.
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Zhao
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: Anticancer; Conformational constraint; Histone methyltransferase; Lysine specific demethylase 1 (LSD1)