Abstract 3255: Tetrahydropyridine derivatives: Novel and potent histone demethylase LSD1 inhibitors

Abstract Flavin-dependent histone demethylases play an important role in epigenetic gene regulation. The most studied enzyme, LSD1 (KDM1), catalyzes the oxidative demethylation of methylated Lys4 of histone H3. Known LSD1 inhibitors also inhibit other flavin-dependent enzymes, in particular monoamine oxidase (MAO). Therefore, selective inhibition of LSD1 is a significant drug discovery target. We designed, synthesized and evaluated in vitro a series of eleven N-substituted tetrahydropyridines as inhibitors of flavin-dependent enzymes. Complete chemical structures of the compounds used will be disclosed at the time of presentation. The inhibition of LSD1 was measured in rat glioma C6 cells. Briefly, cells grown in serum-free medium were treated with the inhibitors for 24 h, and the level of Lys4 dimethylated form of histone H3 was measured by immunoblot. MAO A activity was determined using human recombinant enzyme with kynuramine as substrate. The most selective among the inhibitors showed low nanomolar potency toward LSD1 and weak inhibition of MAO A. The observed high potency and substrate selectivity justifies further evaluation of the drug discovery potential of the tetrahydropyridine scaffold. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3255. doi:10.1158/1538-7445.AM2011-3255