A New Class of BRCA1 Mimetics for ERα-Positive Breast Cancer Therapy: Design, Synthesis, In Silico Screening, In...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Estrogen receptor alpha (ERα) is a key target in ER-positive breast cancer.
• Breast Cancer Gene 1 (BRCA1) can inhibit ERα activity by blocking cyclin D1 interaction.
• Developing BRCA1 mimetics offers a novel therapeutic strategy distinct from conventional antiestrogen drugs.

Purpose of the Study:

• To synthesize and evaluate novel coumarin thiosemicarbazone hybrids as potential BRCA1 mimetics.
• To identify lead compounds targeting ERα repression for ER-positive breast cancer treatment.
• To explore a new mechanism of action distinct from existing antiestrogen therapies.

Main Methods:

• Synthesis of coumarin thiosemicarbazone hybrids from 7-hydroxy 4-methyl coumarin/4-hydroxy coumarin and thiosemicarbazide derivatives.
• In vitro evaluation of ERα repression activity and determination of IC50 values.
• Gene expression analysis (cyclin D1, BCL2), molecular docking, MMGBSA, and in silico ADMET profiling.

Main Results:

• Compounds 9b, 9l, and 9m demonstrated significant ERα repression potency (IC50 values 14.49 µM, 35.08 µM, 42.12 µM, respectively), comparable to raloxifene.
• Compounds 9b, 9l, and 9m effectively downregulated cyclin D1 and BCL2 gene expression.
• Molecular docking and ADMET studies indicated favorable interactions with ERα and good druggability/safety profiles.

Conclusions:

• Coumarin thiosemicarbazone hybrids 9b, 9l, and 9m are identified as promising lead molecules for novel ERα inhibitors.
• These compounds act as BRCA1 mimetics, offering a novel therapeutic approach for ER-positive breast cancer.
• The developed compounds represent a new class of potential therapeutics targeting ERα repression.