Identification of Small Molecule Modulators of Gene Transcription with Anticancer Activity

Epigenetic regulation of gene expression
is essential in many biological
processes, and its deregulation contributes to pathology including
tumor formation. We used an image-based cell assay that measures the
induction of a silenced GFP-estrogen receptor reporter to identify
novel classes of small molecules involved in the regulation of gene
expression. Using this Locus Derepression assay, we queried 283,122
compounds by quantitative high-throughput screening evaluating compounds
at multiple concentrations. After confirmation and independent validation,
the Locus Derepression assay identified 19 small molecules as new
actives that induce the GFP message over 2-fold. Viability assays
demonstrated that 17 of these actives have anti-proliferative activity,
and two of them show selectivity for cancer versus patient-matched
normal cells and cause unique changes in gene expression patterns
in cancer cells by altering histone marks. Hence, these compounds
represent chemical tools for understanding the molecular mechanisms
of epigenetic control of transcription and for modulating cell growth
pathways.