Identification of Jumonji AT-Rich Interactive Domain
1A Inhibitors and Their Effect on Cancer Cells
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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 <b>6j</b>, which
selectively inhibits JARID1A over three other JHDM family members.
Compound <b>7j</b>, a prodrug form of compound <b>6j</b>, induced a selective increase in the level of trimethylation of
histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound <b>7j</b> 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