TY - JOUR
T1 - Identification of small molecule modulators of gene transcription with anticancer activity
AU - Tran, Tram Anh
AU - Wichterman-Kouznetsova, Jennifer
AU - Varghese, Diana
AU - Huang, Ruili
AU - Huang, Wenwei
AU - Becker, Matthias
AU - Austin, Christopher P.
AU - Inglese, James
AU - Johnson, Ronald L.
AU - Martinez, Elisabeth D.
N1 - Publisher Copyright:
© 2014 American Chemical Society.
PY - 2014/11/21
Y1 - 2014/11/21
N2 - 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.
AB - 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.
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U2 - 10.1021/cb500532x
DO - 10.1021/cb500532x
M3 - Article
C2 - 25188650
AN - SCOPUS:84914158936
SN - 1554-8929
VL - 9
SP - 2603
EP - 2611
JO - ACS chemical biology
JF - ACS chemical biology
IS - 11
ER -