Targeting aromatase to restrain oestrogen production and developing efficacious interventions against ER-positive...

Area of Science:

• Medicinal Chemistry
• Oncology
• Drug Discovery

Background:

• Estrogen receptor-positive (ER+) breast cancer is the most common type.
• Selective estrogen receptor modulator (SERM) drugs like tamoxifen are effective but face clinical resistance.
• Aromatase inhibitors offer an alternative treatment strategy by blocking estrogen production.

Purpose of the Study:

• To develop novel compounds targeting aromatase for ER+ breast cancer treatment.
• To identify potent aromatase inhibitors with potential therapeutic applications.
• To evaluate the drug-like properties of newly synthesized compounds.

Main Methods:

• Synthesis of novel compounds based on aromatase's mode of action.
• In vitro evaluation of aromatase inhibition (IC50 values).
• Assessment of tumor growth inhibitory activity against breast cancer cell lines.
• Physicochemical and ADME property evaluation, including plasma protein binding, HSA binding, kinetic studies, solubility, and molecular modeling.

Main Results:

• Three potent compounds (5d, 5e, 7d) were identified with IC50 values of 61.0, 83.0, and 54.0 nM for aromatase, respectively.
• Compounds exhibited appreciable tumor growth inhibitory activities against breast cancer cell lines.
• Physicochemical and molecular modeling studies indicated favorable drug-like properties, supporting their potential as therapeutic agents.

Conclusions:

• The novel compounds demonstrate significant potential as aromatase inhibitors for treating ER+ breast cancer.
• These compounds represent promising candidates for further development to overcome tamoxifen resistance.
• The identified compounds possess favorable physicochemical and ADME profiles, suggesting suitability for drug development.