Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer

Angelo Spinello, Silvia Martini, Federico Berti, Marzia Pennati, Matic Pavlin, Jacopo Sgrignani, Giovanni Grazioso, Giorgio Colombo, Nadia Zaffaroni, Alessandra Magistrato

Research output: Contribution to journalArticle

Abstract

Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance.

Original languageEnglish
Pages (from-to)253-262
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume168
DOIs
Publication statusPublished - Apr 15 2019

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Keywords

  • Aromatase
  • Aromatase inhibitors
  • Breast cancer
  • Cytochromes P450
  • Docking
  • Mixed inhibition mechanism
  • Molecular dynamics
  • Resistance onset

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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