Benzothiophene nucleus in target-directed anti-cancer drug discovery

The benzo[b]thiophene scaffold has emerged as a privileged chemotype in target-directed anticancer drug discovery because of its structural versatility and distinctive sulfur-centered interactions that support selective target binding. This review provides a focused, mechanism-based analysis of benzothiophene derivatives developed as anti-cancer agents, emphasizing compounds with experimentally validated molecular targets and confirmed cellular activity rather than nonspecific cytotoxins. Benzothiophenes have been designed to modulate diverse oncogenic targets, including receptor and non-receptor kinases, STAT3, estrogen receptor pathways, epigenetic regulators, metabolic enzymes, tubulin, and DNA-associated systems. Many derivatives show nanomolar potency, pathway-selective effects, in vivo anti-tumor activity, improved selectivity, and enhanced metabolic stability. Raloxifene remains the only benzothiophene-based drug approved for an oncological indication, highlighting both the scaffold’s clinical promise and the translational barriers that have limited its broader therapeutic advancement. This review also examines key structure–activity relationships, binding determinants, and optimization strategies guiding benzothiophene-based anti-cancer therapeutics. • This review provides a target-directed analysis of benzothiophenes in cancer. • Only compounds with validated mechanisms and cellular efficacy are included. • Diverse oncogenic targets are critically and systematically covered. • Structure–activity relationships and binding determinants are analyzed. • Translational challenges beyond Raloxifene approval are discussed.