Cutting-edge design approaches for steroidal aromatase inhibitors: new horizons for hormone-dependent cancer

Aromatase inhibitors (AIs) are a group of drugs used to cease the production of estrogens that have been used to treat mainly post-menopausal women with both early and advanced estrogen receptor positive (ER+) breast cancer for more than 40 years. They are the first-line therapy for hormone-dependent cancers either alone or in combination with other therapies. This review aims to demonstrate the relevance of research on steroidal AIs.

This work focuses on steroidal AIs and aims to provide a comprehensive explanation of the most potent ones (IC₅₀ < 10 µM), the respective structure-activity relationships (SAR), and the particular biological mechanisms of action, published during the last 20 years, from 2005 until June 2025. The literature search was made on the Web of Science database, using the topic 'steroidal aromatase inhibitors.'

Potent hit steroidal AIs have been discovered. However, further studies are needed, including tests on more complex models, namely using 3D cell lines and organoids as well as animal studies, with the aim of progressing on the drug discovery process, ultimately to discover new potent steroidal AIs with less side effects, especially those related to bone and cardiovascular health and capable to overcome endocrine resistance.