Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells

Yukihiro Itoh; Hideyuki Sawada; Miki Suzuki; Toshifumi Tojo; Ryuzo Sasaki; Makoto Hasegawa; Tamio Mizukami; Takayoshi Suzuki

doi:10.1021/acsmedchemlett.5b00083

Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells

ACS Med Chem Lett. 2015 Apr 23;6(6):665-70. doi: 10.1021/acsmedchemlett.5b00083. eCollection 2015 Jun 11.

Authors

Yukihiro Itoh¹, Hideyuki Sawada¹, Miki Suzuki¹, Toshifumi Tojo¹, Ryuzo Sasaki², Makoto Hasegawa², Tamio Mizukami², Takayoshi Suzuki³

Affiliations

¹ Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
² Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology , 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
³ 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.

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.

Keywords: Epigenetics; drug design; histone demethylase.