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

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

Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1‑Selective Inactivators

Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide <b>3</b>, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide <b>3</b> is a mechanism-based LSD1 inhibitor. Furthermore, peptides <b>37</b> and <b>38</b>, which consist of cell-membrane-permeable oligoarginine conjugated with peptide <b>3</b>, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide <b>37</b> decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1