Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 6, Issue 6, Pages 665-670Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00083
Keywords
Epigenetics; histone demethylase; drug design
Categories
Funding
- CREST, JST
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Kyoto Prefectural Public University Corporation for Young Researcher Grant
- Grants-in-Aid for Scientific Research [25640093] Funding Source: KAKEN
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Jumonji AT-rich interactive domain IA (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 JARIDIA 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 JARIDIA inhibitors have potential as anticancer agents.
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