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Article

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

Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada
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Author to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(2), 579; https://doi.org/10.3390/ijms19020579
Received: 4 January 2018 / Revised: 7 February 2018 / Accepted: 9 February 2018 / Published: 15 February 2018
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 clinical settings. Overall, this study reports the development of a novel class of ERα AF2 inhibitors, which have the potential to effectively inhibit ERα activity by a unique mechanism and to circumvent the issue of mutation-driven resistance in breast cancer. View Full-Text
Keywords: breast cancer; estrogen receptor; hormone resistance; small molecule inhibitors; mutations; in silico modelling; activation function-2 (AF2) site breast cancer; estrogen receptor; hormone resistance; small molecule inhibitors; mutations; in silico modelling; activation function-2 (AF2) site
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MDPI and ACS Style

Singh, K.; Munuganti, R.S.N.; Lallous, N.; Dalal, K.; Yoon, J.S.; Sharma, A.; Yamazaki, T.; Cherkasov, A.; Rennie, P.S. Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-α in Hormone-Resistant Breast Cancers. Int. J. Mol. Sci. 2018, 19, 579. https://doi.org/10.3390/ijms19020579

AMA Style

Singh K, Munuganti RSN, Lallous N, Dalal K, Yoon JS, Sharma A, Yamazaki T, Cherkasov A, Rennie PS. Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-α in Hormone-Resistant Breast Cancers. International Journal of Molecular Sciences. 2018; 19(2):579. https://doi.org/10.3390/ijms19020579

Chicago/Turabian Style

Singh, Kriti; Munuganti, Ravi S.N.; Lallous, Nada; Dalal, Kush; Yoon, Ji S.; Sharma, Aishwariya; Yamazaki, Takeshi; Cherkasov, Artem; Rennie, Paul S. 2018. "Benzothiophenone Derivatives Targeting Mutant Forms of Estrogen Receptor-α in Hormone-Resistant Breast Cancers" Int. J. Mol. Sci. 19, no. 2: 579. https://doi.org/10.3390/ijms19020579

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