A New Class of BRCA1 Mimetics for ERα-Positive Breast Cancer Therapy: Design, Synthesis, In Silico Screening, In Vitro Assay, and Gene Expression Analysis

Breast Cancer Gene 1 (BRCA1) offers a potential approach for ERα repression by blocking cyclin D1's interaction with ERα, which prevents cells from growing and dividing too rapidly or uncontrollably. When BRCA1 levels are low, BRCA1 mimetics fit into the BRCA1-binding pocket within ERα, mimicking the ability of BRCA1 to inhibit ERα activity. This study aims to identify a novel class of lead molecules for BRCA1 mimetics for ER-positive breast cancer, distinct from conventional antiestrogen therapies in their mechanism of action. In this article, coumarin thiosemicarbazone hybrids were synthesized from 7-hydroxy 4-methyl coumarin/4-hydroxy coumarin and thiosemicarbazide with different aldehydes and evaluated for their ERα repression activity. The most active compounds in the series, <b>9b</b>, <b>9l</b>, and <b>9m</b>, exhibited significant potency with an IC₅₀ value of 14.49 µM, 35.08 µM and 42.12 µM, respectively, compared to raloxifene (reported) as the positive control with an IC₅₀ value of 13.7 µM. The gene expression study confirmed the downregulation of the cyclin D1 gene for the compounds <b>9l</b> (-0.217) and <b>9m</b> (-0.214). Similarly, the downregulation of the BCL2 gene for the compounds <b>9b</b> (-0.373), <b>9l</b> (-0.320), and <b>9m</b> (-0.376). Also, molecular docking studies and MMGBSA were performed to determine key interactions between compounds and ERα at the BRCA1 binding pocket (AA 338-387). In silico, ADMET properties were executed to illustrate the druggability and safety of the novel derivatives. In silico, in vitro, and gene expression studies revealed that among all the compounds, <b>9b</b>, <b>9l</b>, and <b>9m</b> are promising candidates for the development of lead molecules targeting ERα inhibitors for breast cancer treatment. Moreover, the concept of ERα repression with small molecules as BRCA1 mimetics is novel. In general, it can be concluded that these compounds can serve as promising leads to the design of potential BRCA1 mimetics.