Heterocyclic scaffolds targeting IDO1: progress in medicinal chemistry and clinical development

AIM: This review mainly aims to systematically compile and analyze recently developed indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors reported over the past 5 years, with emphasis on heterocyclic scaffold-based classification, structure-activity relationships (SAR), and therapeutic relevance. METHODS: A comprehensive literature survey was conducted to identify IDO1 inhibitors, which were categorized based on their core heterocyclic scaffolds. Studies involving biological evaluation, SAR analysis, and molecular docking were critically assessed. RESULTS: IDO1 inhibitors were classified into diverse scaffolds, including indoles, imidazoles, phenyl urea-benzimidazoles, azoles, imidazopyridines, benzofurans, quinolines, pyrimidines, erlotinib-based analogues, naphthoquinones, hydroxyamidine derivatives, quinazolines, and sulfonamide chromone-oxime analogues. Key SAR trends and biological activities were highlighted. Clinically investigated inhibitors such as indoximod, epacadostat, navoximod, LY3381916, linrodostat, and PF-06840003 were also evaluated for therapeutic outcomes. CONCLUSION: This review provides an updated overview of IDO1 inhibitor design and development, offering valuable insights into scaffold optimization and future directions for developing effective anticancer agents targeting tumor immunosuppression.