Shyam Sundar Pottabathula, Selvaraj Jubie, Alagarsamy Veerachamy, Solomon Viswas Raja, Natarajan Jawahar
Department of Pharmaceutical Chemistry, Vasantidevi Patil Institute of Pharmacy, Kodoli 416114, Maharastra, India.
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty 643001, Tamilnadu, India.
Life (Basel). 2025 Apr 1;15(4):581. doi: 10.3390/life15040581.
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, , , and , exhibited significant potency with an IC value of 14.49 µM, 35.08 µM and 42.12 µM, respectively, compared to raloxifene (reported) as the positive control with an IC value of 13.7 µM. The gene expression study confirmed the downregulation of the cyclin D1 gene for the compounds (-0.217) and (-0.214). Similarly, the downregulation of the BCL2 gene for the compounds (-0.373), (-0.320), and (-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, , , and 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.
乳腺癌1号基因（BRCA1）通过阻断细胞周期蛋白D1与雌激素受体α（ERα）的相互作用，为抑制ERα提供了一种潜在方法，这种相互作用可防止细胞过度快速或不受控制地生长和分裂。当BRCA1水平较低时，BRCA1模拟物可嵌入ERα内的BRCA1结合口袋，模拟BRCA1抑制ERα活性的能力。本研究旨在为ER阳性乳腺癌的BRCA1模拟物鉴定一类新型先导分子，其作用机制不同于传统抗雌激素疗法。在本文中，香豆素硫代氨基脲杂化物由7 - 羟基 - 4 - 甲基香豆素/4 - 羟基香豆素与硫代氨基脲和不同醛类合成，并评估其对ERα的抑制活性。该系列中活性最高的化合物，即[具体化合物1]、[具体化合物2]和[具体化合物3]，与作为阳性对照的雷洛昔芬（报道的IC值为13.7 μM）相比，分别表现出显著的效力，IC值为14.49 μM、35.08 μM和42.12 μM。基因表达研究证实，化合物[具体化合物1]（-0.217）和[具体化合物2]（-0.214）可下调细胞周期蛋白D1基因。同样，化合物[具体化合物1]（-0.373）、[具体化合物2]（-0.320）和[具体化合物3]（-0.376）可下调BCL2基因。此外，还进行了分子对接研究和MMGBSA分析，以确定化合物与ERα在BRCA1结合口袋（氨基酸338 - 387）处的关键相互作用。在计算机模拟中，执行了ADMET性质分析以说明新型衍生物的成药性和安全性。计算机模拟、体外实验和基因表达研究表明，在所有化合物中，[具体化合物1]、[具体化合物2]和[具体化合物3]是开发针对乳腺癌治疗的ERα抑制剂先导分子的有前途的候选物。此外，以小分子作为BRCA1模拟物抑制ERα的概念是新颖的。总体而言，可以得出结论，这些化合物可作为设计潜在BRCA1模拟物的有前途的先导物。
