Toxicity testing on zebrafish embryos revealed that Y134 has a significantly better safety profile than raloxifene. Y134 also induced apoptosis in hepatoma cells without having an effect on cell cycle regulation. Suppression of AhR expression strongly reduced apoptosis induced by Y134, indicating the requirement of AhR for Y134-induced apoptosis.
We identified Y134 as a raloxifene analog that activates AhR-mediated transcriptional activity and induces apoptosis in MDA-MB-231 human triple negative breast cancer cells.
We performed structure-activity studies with seven raloxifene analogs to better understand the structural requirements of raloxifene for induction of AhR-mediated transcriptional activity and apoptosis. Raloxifene induces apoptosis in estrogen receptor-negative human cancer cells through the AhR. We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the aryl hydrocarbon receptor (AhR). In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same.
With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women.
0 kommentar(er)
