Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-α in Hormone-Resistant Breast Cancers.

International Journal of Molecular Sciences
Kriti SinghPaul S Rennie

Abstract

Estrogen receptor-α positive (ERα⁺) breast cancers represent 75% of all invasive breast cancer cases, while de novo or acquired resistance to ER-directed therapy is also on the rise. Numerous factors contribute to this phenomenon including the recently-reported ESR1 gene mutations such as Y537S, which amplifies co-activator interactions with ERα and promotes constitutive activation of ERα function. Herein, we propose that direct targeting of the activation function-2 (AF2) site on ERα represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer. A systematic computer-guided drug discovery approach was employed to develop a potent ERα inhibitor that was extensively evaluated by a series of experiments to confirm its AF2-specific activity. We demonstrate that the developed small-molecule inhibitor effectively prevents ERα-coactivator interactions and exhibits a strong anti-proliferative effect against tamoxifen-resistant cells, as well as downregulates ERα-dependent genes and effectively diminishes the receptor binding to chromatin. Notably, the identified lead compound successfully inhibits known constitutively-active, resistance-associated mutant forms of ERα observed in clinic...Continue Reading

References

Nov 26, 1998·The New England Journal of Medicine·C K Osborne
Jan 23, 2004·Journal of Medicinal Chemistry·Alice L RodriguezJohn A Katzenellenbogen
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Apr 20, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rakesh KumarSuresh K Rayala
Mar 7, 2006·Nature Reviews. Drug Discovery·Gergely SzakácsMichael M Gottesman
Jun 20, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yong WangThomas P Burris
Aug 19, 2006·Breast Disease·Joan S Lewis-Wambi, V Craig Jordan
Jan 24, 2007·Breast Cancer Research : BCR·Lisa K DunnwaldChristopher I Li
Jun 15, 2007·Bioorganic & Medicinal Chemistry Letters·Hai-Bing ZhouJohn A Katzenellenbogen
Nov 10, 2009·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Leo A NiemeierRohit Bhargava
Jul 7, 2011·Current Pharmaceutical Design·Guy LeclercqYves Jacquot
Mar 16, 2012·International Journal of Biological Sciences·Claire A WalshJianming Xu
May 17, 2012·The Journal of Biological Chemistry·Milu T CherianDavid J Shapiro
Mar 28, 2013·Endocrine-related Cancer·Etienne Leygue, Leigh C Murphy
Aug 21, 2013·Molecular and Cellular Endocrinology·Lars-Arne HaldosénKarin Dahlman-Wright
Nov 5, 2013·Nature Genetics·Dan R RobinsonArul M Chinnaiyan
Nov 5, 2013·Nature Genetics·Weiyi ToySarat Chandarlapaty
Jan 9, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rinath JeselsohnVincent A Miller
May 29, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Harold J BursteinJennifer J Griggs
Apr 4, 2015·Expert Opinion on Drug Discovery·Samuel Genheden, Ulf Ryde
Oct 20, 2015·Journal of Chemical Information and Modeling·Teague Sterling, John J Irwin
Dec 18, 2016·Cancer Discovery·Weiyi ToySarat Chandarlapaty
May 26, 2017·Breast Cancer Research : BCR·Amir BahreiniSteffi Oesterreich

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Citations

Mar 31, 2019·Medicinal Research Reviews·Michael HsingArtem Cherkasov
Jan 18, 2020·International Journal of Molecular Sciences·André Fischer, Martin Smieško
Oct 18, 2018·International Journal of Molecular Sciences·Yasuhiro MikiKiyoshi Ito
Aug 6, 2020·International Journal of Molecular Sciences·Mari Ishigami-Yuasa, Hiroyuki Kagechika
Jun 18, 2020·International Journal of Molecular Sciences·Divya BafnaArtem Cherkasov
Jun 5, 2019·Molecular and Cellular Endocrinology·Kornelia J SkowronTerry W Moore

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Methods Mentioned

BETA
biolayer interferometry
fluorescence resonance
two-hybrid
Assay
immunoprecipitation
pull down
ChIP
two hybrid

Software Mentioned

ChemAxon
GraphPad
Glide SP
Instant JChem
GraphPad Prism

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