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  3. Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer

Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer

  • Eur J Med Chem. 2021 Nov 15:224:113733. doi: 10.1016/j.ejmech.2021.113733.
Jessica Caciolla 1,  Silvia Martini 2,  Angelo Spinello 3,  Matic Pavlin 4,  Eleonora Turrini 5,  Federica Simonelli 3,  Federica Belluti 1,  Angela Rampa 1,  Alessandra Bisi 1,  Carmela Fimognari 5,  Nadia Zaffaroni 2,  Silvia Gobbi 6,  Alessandra Magistrato 7
Affiliations

Affiliations

  • 1 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
  • 2 Fondazione IRCSS Istituto Nazionale Dei Tumori, Via Amadeo 42, 20113, Milano, Italy.
  • 3 National Research Council of Italy Institute of Materials (CNR-IOM) C/o SISSA, Via Bonomea 265, 34136, Trieste, Italy.
  • 4 National Research Council of Italy Institute of Materials (CNR-IOM) C/o SISSA, Via Bonomea 265, 34136, Trieste, Italy; Laboratory of Microsensor Structures and Electronics, Faculty of Electrical Engineering, University of Ljubljana, Tržaška Cesta 25, SI-1000 Ljubljana, Slovenia.
  • 5 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso D'Augusto 237, 47921, Rimini, Italy.
  • 6 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: silvia.gobbi@unibo.it.
  • 7 National Research Council of Italy Institute of Materials (CNR-IOM) C/o SISSA, Via Bonomea 265, 34136, Trieste, Italy. Electronic address: alessandra.magistrato@sissa.it.
PMID: 34364162 DOI: 10.1016/j.ejmech.2021.113733
Abstract

Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) Enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico design, synthesis, biological evaluation and an atomic-level characterization of the binding and inhibition mechanism of twelve structurally related drug-candidates enable the discovery of multiple compounds active on both AR and ERα in the sub-μM range. The best drug-candidate 3a displayed a balanced low-nanomolar IC50 towards the two targets, SERM activity and moderate selectivity towards a BC cell line. Moreover, most of the studied compounds reduced ERα levels, suggesting a potential SERD activity. This study dissects the key structural traits needed to obtain optimal dual acting drug-candidates, showing that multitarget compounds may be a viable therapeutic option to counteract ER + BC.

Keywords

Aromatase inhibitors; Molecular dynamics; Multitarget; QM/MM; SERD; SERM; breast cancer.

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