title: 3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1.
abstract: Methylation of histone lysine residues plays important roles in gene expression regulation as well as cancer initiation. Lysine specific demethylase 1 (LSD1) is responsible for maintaining balanced methylation levels at histone H3 lysine 4 (H3K4). LSD1 is a drug target for certain cancers, due to important functions of methylated H3K4 or LSD1 overexpression. We report the design, synthesis, and structure-activity relationships of 3-(piperidin-4-ylmethoxy)pyridine containing compounds as potent LSD1 inhibitors with Ki values as low as 29 nM. These compounds exhibited high selectivity (>160×) against related monoamine oxidase A and B. Enzyme kinetics and docking studies suggested they are competitive inhibitors against a dimethylated H3K4 substrate and provided a possible binding mode. The potent LSD1 inhibitors can increase cellular H3K4 methylation and strongly inhibit proliferation of several leukemia and solid tumor cells with EC50 values as low as 280 nM, while they had negligible effects on normal cells.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Fangrui
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008745:Methylation; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C000607644:3-(piperidin-4-ylmethoxy)pyridine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006657:Histones; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; D011725:Pyridines; D056466:Histone Demethylases; C495195:KDM1A protein, human