A quantitative high-throughput screen identifies potential epigenetic modulators of gene expression.

Analytical Biochemistry
Ronald L JohnsonElisabeth D Martinez

Abstract

Epigenetic regulation of gene expression is essential in embryonic development and contributes to cancer pathology. We used a cell-based imaging assay that measures derepression of a silenced green fluorescent protein (GFP) reporter to identify novel classes of compounds involved in epigenetic regulation. This locus derepression (LDR) assay was screened against a 69,137-member chemical library using quantitative high-throughput screening (qHTS), a titration-response method that assays compounds at multiple concentrations. From structure-activity relationships of the 411 actives recovered from the qHTS, 6 distinct chemical series were chosen for further study. A total of 48 qHTS actives and analogs were counterscreened using the parental line of the LDR cells, which lack the GFP reporter. Three series-8-hydroxy quinoline, quinoline-8-thiol, and 1,3,5-thiadiazinane-2-thione-were not fluorescent and reconfirmed activity in the LDR cells. The three active series did not inhibit histone deacetylase activity in nuclear extracts or reactivate the expression of the densely methylated p16 gene in cancer cells. However, one series induced expression of the methylated CDH13 gene and inhibited the viability of several lung cancer lines at ...Continue Reading

References

Jan 1, 1996·Journal of Cellular Biochemistry. Supplement·R M PhelpsJ L Mulshine
Dec 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·A BedalovJ A Simon
Mar 27, 2002·Anti-cancer Drugs·David M Vigushin, R Charles Coombes
Sep 26, 2002·The Journal of Biological Chemistry·Kevin J BittermanDavid A Sinclair
Nov 14, 2002·The Biochemical Journal·Annemieke J M de RuijterAndré B P van Kuilenburg
Oct 8, 2003·Current Medicinal Chemistry·Michael Curtin, Keith Glaser
Feb 10, 2004·Proceedings of the National Academy of Sciences of the United States of America·David AngeliEduardo D Sontag
Jul 21, 2004·Proceedings of the National Academy of Sciences of the United States of America·Jaejoon WonTae Kook Kim
Aug 18, 2004·Biochemical Pharmacology·Fiona McLaughlin, Nicholas B La Thangue
May 6, 2005·Assay and Drug Development Technologies·Patrick H Cleveland, Patricia J Koutz
Sep 16, 2005·The Journal of Steroid Biochemistry and Molecular Biology·Elisabeth D MartinezGordon L Hager
Oct 18, 2005·Molecular Cancer Therapeutics·Lindsay StimsonG Wynne Aherne
Jan 7, 2006·Nature Reviews. Cancer·Saverio Minucci, Pier Giuseppe Pelicci
May 23, 2006·Assay and Drug Development Technologies·Wayne P Bowen, Paul G Wylie
Jul 26, 2006·Proceedings of the National Academy of Sciences of the United States of America·James IngleseChristopher P Austin
Nov 18, 2006·Methods in Enzymology·Elisabeth D MartinezGordon L Hager
Feb 3, 2007·Nature Reviews. Drug Discovery·Steven GrantPeter Kirkpatrick
Feb 27, 2007·Cell·Peter A Jones, Stephen B Baylin
Feb 27, 2007·Cell·Tony Kouzarides
Apr 28, 2007·The Cancer Journal·Bodo BruecknerFrank Lyko

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Citations

May 17, 2011·Journal of Medicinal Chemistry·Chun-Wa ChungEdwige Nicodeme
Oct 13, 2012·Journal of Natural Products·Youcai HuJohn B MacMillan
Nov 24, 2011·Organic Letters·Youcai Hu, John B MacMillan
Dec 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Michael D SlackSteven J Altschuler
Nov 28, 2008·Assay and Drug Development Technologies·Sam MichaelAnton Simeonov
Jan 15, 2011·Journal of Biomedicine & Biotechnology·Anne M BestElisabeth D Martinez
Apr 27, 2010·Current Opinion in Chemical Biology·Natasha ThorneJames Inglese
Jan 19, 2010·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Adi F GazdarJohn D Minna
Sep 13, 2012·Biochimie·Christina GrosPaola B Arimondo
Feb 6, 2015·Assay and Drug Development Technologies·Paul G WylieWayne P Bowen
May 10, 2016·Nature Chemical Biology·Sara SdelciStefan Kubicek
Nov 20, 2013·Journal of Biomolecular Screening·Ji-Hu ZhangDouglas S Auld
Apr 18, 2008·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Attila Tárnok
Apr 20, 2018·Environmental Health Perspectives·Michelle M AngrishBrian N Chorley
Feb 12, 2013·Natural Product Reports·Fanny L CherblancMatthew J Fuchter
Feb 17, 2021·Cell Chemical Biology·Jayme L DahlinBridget K Wagner
Jul 23, 2008·ACS Chemical Biology·Christen Brownlee
Sep 5, 2014·ACS Chemical Biology·Tram Anh TranElisabeth D Martinez

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