Mechanisms of allosteric and mixed mode aromatase inhibitors

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Aromatase (CYP19) is crucial for estrogen biosynthesis and a key target in hormone-dependent breast cancer.
• Current aromatase inhibitors face challenges including adverse effects and drug resistance.

Purpose of the Study:

• To discover novel non-steroidal aromatase inhibitors using virtual screening.
• To identify new chemical scaffolds for breast cancer therapy with potentially improved safety profiles.

Main Methods:

• Virtual screening targeting a predicted cytochrome P450 reductase binding site on aromatase.
• In vitro assays to determine inhibitor potency and inhibition type (mixed-type and competitive-type).
• Molecular modeling to predict ligand binding sites.

Main Results:

• Four novel non-steroidal aromatase inhibitors were identified.
• The most potent inhibitors, AR11 and AR13, demonstrated comparable potency to endoxifen.
• Inhibitors exhibited mixed-type and competitive-type inhibition, suggesting binding at multiple sites near the catalytic core.
• The cytochrome P450 reductase-CYP19 coupling interface was identified as a potential low-affinity binding site.

Conclusions:

• Novel non-steroidal aromatase inhibitors targeting aromatase (CYP19) have been discovered.
• These inhibitors may offer alternative therapeutic options for breast cancer, potentially with distinct adverse effect profiles.
• The findings highlight the significance of the reductase binding interface as a ligand-binding site on aromatase.