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Int. J. Mol. Sci. 2018, 19(2), 579; https://doi.org/10.3390/ijms19020579

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
These authors contributed equally to this work.
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Received: 4 January 2018 / Revised: 7 February 2018 / Accepted: 9 February 2018 / Published: 15 February 2018
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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 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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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.

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