Abstract 4805: A quantitative high-throughput screen identifies novel potential epigenetic modulators of gene transcription

Abstract

Abstract Epigenetic regulation of gene expression is important in many biological processes including tumor formation. While some key modulators of epigenetic control like histone deacetylases and DNA methyltransferases are the subject of intensive research, little else is known of other targets or modifications that regulate this process. We used an image-based cell assay that measures induction of a silenced GFP-estrogen receptor (ER) reporter to identify novel classes of compounds involved in epigenetic regulation. This Locus Derepression (LDR) assay was screened against 282,000 compounds using quantitative high-throughput screening, a method that assays compounds at multiple concentrations. Structure-activity relationships of the 680 actives recovered from the screen indicated 127 clusters and 110 singletons. Over 200 compounds were retested in the LDR cells and were counter-screened against the parental line to identify fluorescent artifacts. Of the 72 compounds that retested as active and nonfluorescent, 57 were tested as independent samples to confirm activity. Confirmation studies indicated 23 compounds showed consistent activity in LDR cells and were not fluorescent. Confirmed actives are being characterized further to identify the targets and pathways these molecules modulate. These compounds represent important tool compounds for understanding the molecular mechanisms of epigenetic control of transcription. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4805.