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Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors

  • Jessica Caciolla
    Jessica Caciolla
    Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, via Belmeloro 6, 40126 Bologna, Italy
  • Angelo Spinello
    Angelo Spinello
    CNR-IOM Democritos c/o International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
  • Silvia Martini
    Silvia Martini
    Fondazione IRCSS Istituto Nazionale dei Tumori, via Amadeo 42, 20113 Milano, Italy
  • Alessandra Bisi
    Alessandra Bisi
    Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, via Belmeloro 6, 40126 Bologna, Italy
  • Nadia Zaffaroni
    Nadia Zaffaroni
    Fondazione IRCSS Istituto Nazionale dei Tumori, via Amadeo 42, 20113 Milano, Italy
  • Silvia Gobbi*
    Silvia Gobbi
    Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, via Belmeloro 6, 40126 Bologna, Italy
    *Email: [email protected]
    More by Silvia Gobbi
  • , and 
  • Alessandra Magistrato*
    Alessandra Magistrato
    CNR-IOM Democritos c/o International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
    *Email: [email protected]
Cite this: ACS Med. Chem. Lett. 2020, 11, 5, 732–739
Publication Date (Web):March 23, 2020
https://doi.org/10.1021/acsmedchemlett.9b00591
Copyright © 2020 American Chemical Society

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    Abstract

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    Breast cancer (BC) is the most diffused cancer type in women and the second leading cause of death among the female population. Effective strategies to fight estrogen responsive (ER+) BC, which represents 70% of all BC cases, rely on estrogen deprivation, via the inhibition of the aromatase enzyme, or the modulation of its cognate estrogen receptor. Current clinical therapies significantly increased patient survival time. Nevertheless, the onset of resistance in metastatic BC patients undergoing prolonged treatments is becoming a current clinical challenge, urgently demanding to devise innovative strategies. In this context, here we designed, synthesized, and performed in vitro inhibitory tests on the aromatase enzyme and distinct ER+/ER– BC cell line types of novel azole bridged xanthones. These compounds are active in the low μM range and behave as dual-mode inhibitors, targeting both the orthosteric and the allosteric sites of the enzyme placed along one access channel. Classical and quantum-classical molecular dynamics simulations of the new compounds, as compared with selected steroidal and nonsteroidal inhibitors, provide a rationale to the observed inhibitory potency and supply the guidelines to boost the activity of inhibitors able to exploit coordination to iron and occupation of the access channel to modulate estrogen production.

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    • Experimental procedures for the syntheses and in vitro evaluation of compounds activities and simulation protocol and analysis; cellular proliferation assays, access/egress channels, binding pose, and representative structures; potential off-target interactions of the xanthone derivatives (PDF)

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