title: Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors.
abstract: Selective inhibitors of Jumonji domain-containing protein (JMJD) histone demethylases are candidate anticancer agents as well as potential tools for elucidating the biological functions of JMJDs. On the basis of the crystal structure of JMJD2A and a homology model of JMJD2C, we designed and prepared a series of hydroxamate analogues bearing a tertiary amine. Enzyme assays using JMJD2C, JMJD2A, and prolyl hydroxylases revealed that hydroxamate analogue 8 is a potent and selective JMJD2 inhibitor, showing 500-fold greater JMJD2C-inhibitory activity and more than 9100-fold greater JMJD2C-selectivity compared with the lead compound N-oxalylglycine 2. Compounds 17 and 18, prodrugs of compound 8, each showed synergistic growth inhibition of cancer cells in combination with an inhibitor of lysine-specific demethylase 1 (LSD1). These findings suggest that combination treatment with JMJD2 inhibitors and LSD1 inhibitors may represent a novel strategy for anticancer chemotherapy.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Aichi, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Hamada
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Koshiki
authors.initials: K
authors.lastname: Mino
authors.forename: Koichi
authors.initials: K
authors.lastname: Koseki
authors.forename: Felix
authors.initials: F
authors.lastname: Oehme
authors.forename: Ingo
authors.initials: I
authors.lastname: Flamme
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ozasa
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogasawara
authors.forename: Haruka
authors.initials: H
authors.lastname: Komaarashi
authors.forename: Aiko
authors.initials: A
authors.lastname: Kato
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsumoto
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Sasaki
authors.forename: Tamio
authors.initials: T
authors.lastname: Mizukami
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D056466:Histone Demethylases / Q000037:antagonists & inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000600:Amino Acids, Dicarboxylic; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; C413655:KDM4C protein, human; D011355:Prodrugs; C551947:methyl 3-((9-(dimethylamino)nonanoyl)(hydroxy)amino)propanoate; C551948:methyl 3-((9-(dimethylamino)nonanoyl)(methoxy)amino)propanoate; D015091:beta-Alanine; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C495195:KDM1A protein, human; C494424:KDM4A protein, human; C040947:oxalylglycine