Evolving Strategies for Previously Drugged Therapeutic Targets: Medicinal Chemistry Insights from Paradigmatic Cases.

Previously drugged therapeutic targets have continued to attract substantial scientific and clinical interest, resulting in numerous FDA approvals for new chemical entities (NCEs) over the past 15 years. This sustained productivity demonstrates that these established therapeutic drug targets remain a central foundation of modern drug discovery, supporting not only incremental improvements in efficacy and safety but also the development of innovative medicinal chemistry strategies and novel mechanisms of action. In this Perspective, we provide a comprehensive analysis of the contributions of previously drugged therapeutic targets to FDA-approved small-molecule drugs between 2010 and 2025, with an emphasis on therapeutic innovation based on several representative therapeutic drug targets across central nervous system, infectious disease, and oncology indications. The design principles and translational insights derived from these paradigmatic cases highlight the enduring value of these "evergreen" therapeutic drug targets and may inform future efforts to develop more effective, differentiated, and resistance-resilient therapeutics.