Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers

ABSTRACT

Introduction: The vast majority of breast cancers (BC) are estrogen receptor positive (ER+). The most effective treatments to fight this BC type rely on estrogen deprivation therapy, by inhibiting the aromatase enzyme, which performs estrogen biosynthesis, or on blocking the estrogens signaling path via modulating/degrading the estrogen’s specific nuclear receptor (estrogen receptor-α, ERα). While being effective at early disease stage, patients treated with aromatase inhibitors (AIs) may acquire resistance and often relapse after prolonged therapies.

Areas covered: In this compendium, after an overview of the historical development of the AIs currently in clinical use, and of the computational tools which were used to identify them, the authors focus on current advances in obtaining innovative inhibitors via molecular simulations. These inhibitors may help prevent or delay relapse to AIs.

Expert opinion: BC remains the most diagnosed and the leading cause of death in women. In spite of the success of the adjuvant endocrine therapy, which has enormously prolonged woman’s survival rate, the increasing emergence of the resistance phenomena calls for the development of novel approaches and drugs to fight it. The discovery of the last generation of AIs dates back to two decades ago, underlying a paucity of research efforts.

KEYWORDS:

• Breast cancer
• aromatase inhibitors
• ligand-based and structure-based drug design
• molecular dynamics
• virtual screening
• allostery
• CYP450s

Article highlights

• Endocrine adjuvant therapy using aromatase inhibitors (AIs) is nowadays one of the most effective therapeutic strategy in the treatment of estrogen receptor positive breast cancer (BC).

• Estrogen deprivation in prolonged therapies regimens leads to endocrine resistance and side effects, which urgently calls for the development of the fourth generation of AIs, relying on novel strategies.

• Allosteric modulators of Human Aromatase (HA), exerting a non-active site-directed inhibition mechanism, may offer appealing opportunity to avoid side effects and resistance induced by estrogen deprivation.

• Phosphorylation of HA have been demonstrated to up-regulate estrogen biosynthesis in BC cell lines. Counteracting this pathway remains an unexplored inhibitory opportunity.

• Compounds possessing a dual AI/SERM activity, also able to degrade intrinsically active ERα isoforms, may represent a promising new strategy for BC therapy.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by the Italian Association for Cancer Research via grant number grant no: 17134 as well as by FIRC-AIRC ‘Gianni Bonadonna’ and FIRC-AIRC ‘Mario e Valeria Rindi’ fellowships.