Next Article in Journal
Glycosylation as a Main Regulator of Growth and Death Factor Receptors Signaling
Next Article in Special Issue
ARHGAP15 in Human Breast Carcinoma: A Potent Tumor Suppressor Regulated by Androgens
Previous Article in Journal
Charged N-terminus of Influenza Fusion Peptide Facilitates Membrane Fusion
Previous Article in Special Issue
Discovering the Deregulated Molecular Functions Involved in Malignant Transformation of Endometriosis to Endometriosis-Associated Ovarian Carcinoma Using a Data-Driven, Function-Based Analysis
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
*
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
Show Figures

Graphical abstract

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

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop