title: Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells.
abstract: Jumonji AT-rich interactive domain 1A (JARID1A), one of the jumonji C domain-containing histone demethylase (JHDM) family members, plays key roles in cancer cell proliferation and development of drug tolerance. Therefore, selective JARID1A inhibitors are potential anticancer agents. In this study, we searched for cell-active JARID1A inhibitors by screening hydroxamate compounds in our in-house library and the structural optimization based on docking study of the hit-compound to a homology model of JARID1A. As a result, we identified compound 6j, which selectively inhibits JARID1A over three other JHDM family members. Compound 7j, a prodrug form of compound 6j, induced a selective increase in the level of trimethylation of histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound 7j synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor. These findings support the idea that JARID1A inhibitors have potential as anticancer agents.
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sawada
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tojo
authors.affiliation: Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology , 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Sasaki
authors.affiliation: Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology , 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology , 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan ; CREST, Japan Science and Technology Agency (JST) , 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
keywords: Epigenetics; drug design; histone demethylase