Integrated Scaffold Redesign and iPSC-Based Screening Reveal Potent Antifibrotic Artemisinin Analogs in Systemic Sclerosis Models

To address this unmet medical need, we report an integrated, chemistry-driven discovery platform for function-oriented molecular design and discovery that combines scaffold redesign of a classical natural product pharmacophore with human induced pluripotent stem cell (iPSC)-based phenotypic screening to identify potent antifibrotic agents.

Systematic modification of the artemisinin scaffold led to the identification of 6-aza-artemisinins with markedly enhanced antifibrotic activity, including an N6–N6′ dimeric analog exhibiting high potency at sub-micromolar concentrations. These compounds suppressed collagen production in systemic sclerosis patient-derived fibroblasts and ameliorated fibrosis in a bleomycin-induced murine model, with superior efficacy relative to the clinically used antimalarial drug artesunate.