ABSTRACT Selective estrogen receptor modulators (SERMs) are an important class of drugs mainly useful in the treatment of breast cancer as they act as estrogen antagonists in the breast tissue but have an agonistic activity in bone and the cardiovascular system (CVS). ER‐positive breast cancer, driven by estrogen signaling, is the most prevalent subtype worldwide. SERMs remain essential therapeutics, antagonizing estrogen activity in breast tissue while retaining agonist effects in bone and CVS. While traditional reviews have focused on triphenylethylene and benzothiophene scaffolds, this review provides a novel, insightful comprehensive analysis of emerging heterocyclic SERMS—including indole, benzimidazole, coumarin, benzopyran, organometallic, and phytoestrogen derivatives—linking chemical diversity with tissue‐selective mechanisms and structure–activity relationships. Major limitations include incomplete receptor subtype selectivity, metabolic instability, partial agonism in nontarget tissues, and acquired endocrine resistance driven by ER mutations and growth factor signaling. This work uniquely integrates structural, mechanistic, and therapeutic insights and highlights innovative strategies, including dual SERM‐SERD scaffolds, combination with aromatase inhibitors, and computationally guided subtype‐selective design to overcome resistance, improve potency, and optimize clinical outcomes in ER‐positive breast cancer therapy.
Saini et al. (Sun,) studied this question.