Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors.
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.
Hamada
Shohei
S
Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Aichi, Japan.
Suzuki
Takayoshi
T
Mino
Koshiki
K
Koseki
Koichi
K
Oehme
Felix
F
Flamme
Ingo
I
Ozasa
Hiroki
H
Itoh
Yukihiro
Y
Ogasawara
Daisuke
D
Komaarashi
Haruka
H
Kato
Aiko
A
Tsumoto
Hiroki
H
Nakagawa
Hidehiko
H
Hasegawa
Makoto
M
Sasaki
Ryuzo
R
Mizukami
Tamio
T
Miyata
Naoki
N
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
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