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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Chem. | doi: 10.3389/fchem.2019.00602

Structural, Thermodynamic and Kinetic Traits of Antiestrogen-compounds Selectively Targeting the Y537S Mutant Estrogen Receptor α Transcriptional Activity in Breast Cancer Cell Lines

Matic Pavlin1, Luca Gelsomino2, Ines Barone2, Angelo Spinello1,  Stefania Catalano2, Sebastiano Ando2* and  Alessandra Magistrato1, 3*
  • 1Istituto officina dei materiali (IOM), Italy
  • 2University of Calabria, Italy
  • 3Italian National Research Council (CNR), Italy

The most frequently diagnosed cancers in women are the estrogen receptor (ER)-positive breast cancer subtypes, which are characterized by estrogen dependency for their growth. The mainstay of clinical treatment for this tumor relies on the modulation of ER action or on the suppression of estrogen biosynthesis via the administration of Selective ERα Modulators/Down-regulators (SERMs/SERDs) or aromatase inhibitors, respectively. Nevertheless, de novo and acquired resistance to these therapies frequently occurs and represents a major clinical concern for patient survival. Recently, somatic mutations affecting the hormone-binding domain of ERα (i. e. Y537S, Y537N, D538G) have been associated with endocrine resistance, disease relapse and increased mortality rates. Hence, devising novel therapies against these ERα isoforms represents a daunting challenge.
Here, we identified five molecules active on recurrent Y537S ERα polymorphism by employing in silico virtual screening on commercial databases of molecules, complemented by ER-transactivation and MTT assays in MCF7 and MDA-MB-231 breast cancer cells expressing wild type or mutated ERα. Among them, one molecule selectively targets Y537S ERα without inducing any cytotoxicity in breast cell lines. Multi-microseconds (4.5 µs) of biased and unbiased molecular dynamics provided an atomic-level picture of the structural, thermodynamics (i. e. binding free energies) and the kinetic (i. e. dissociation free energy barriers) of these active ligands as compared to clinically used SERM/SERDs upon binding to wild type and distinct ERα variants (Y537S, Y537N, D538G). This study contributes to a dissection of the key molecular traits needed by drug-candidates to hamper the agonist (active)-like conformation of ERα, normally selected by those polymorphic variants. This information can be useful to discover mutant specific drug-candidates, enabling to move a step forward towards tailored approaches for breast cancer treatment.

Keywords: Estrogen receptor, breast cancer, molecular dynamics, SERM, SERD, In silico screening, Y537S and D538G estrogen receptor

Received: 24 Jun 2019; Accepted: 15 Aug 2019.

Copyright: © 2019 Pavlin, Gelsomino, Barone, Spinello, Catalano, Ando and Magistrato. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Sebastiano Ando, University of Calabria, Arcavacata, 87036, Calabria, Italy,
Mx. Alessandra Magistrato, Italian National Research Council (CNR), Rome, Italy,