Optimization of small molecule degraders and antagonists for targeting estrogen receptor based on breast cancer: current status and future

The estrogen receptor (ER) is a classical protein that plays crucial role in mediating multiple signaling pathways various target organs. It has been shown ER-targeting therapies inhibit breast cancer cell proliferation, enhance neuronal protection, and promote osteoclast formation. Several drugs have designed to specifically ER ER-positive (ER+) cancer, including selective modulators (SERM) such as Tamoxifen. However, the emergence of drug resistance ER+ potential side effects on endometrium which high expression posed significant challenges clinical practice. Recently, novel ER-targeted drugs, namely, degrader (SERD) covalent antagonist (SERCA) promise addressing these concerns. This paper provides comprehensive review structural functions highlights recent advancements SERD SERCA-related small molecule especially focusing their optimization strategies future directions. Additionally, therapeutic SERDs SERCAs other ER-related diseases discussed.