ArticleAngewandte Chemie (International ed. in English)2026
Design, Synthesis, and Structural Evolution of Pseudo-Natural Product IDO1 Inhibitors and Degraders.
Article in Angewandte Chemie (International ed. in English), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Integrated Network Pharmacology and Machine Learning to Reveal the Mechanisms of Schisandrin A Against Triple-Negative Breast Cancer.Journal of cellular and molecular medicine · 2026Article
- Design, Synthesis, and Biological Evaluation of Pseudo-Natural Products Inspired by Aryloctahydroindole Alkaloids.ChemMedChem · 2026Article
- Design, Synthesis, and Structural Evolution of Pseudo-Natural Product IDO1 Inhibitors and Degraders.Angewandte Chemie (International ed. in English) · 2026Article
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Authors and funding
20 authors.
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Abstract
Terpenoid alkaloids are derived from the fusion of structurally diverse terpenoid- and alkaloid moieties. The biologically relevant chemical space defined by this unique natural product (NP) class may be explored beyond the limitations of biosynthetic pathways by means of the pseudo natural product (PNP) principle, i.e., by combination of NP fragments in different arrangements. We describe the design, synthesis and structural evolution of a monoterpene-pyrrolidine PNP collection obtained by functionalization and combination of bicyclic monoterpenes with pyrrolidine alkaloid-derived fragments. Diverse fusion strategies led to the discovery of (-)-myrtenal-pyrrolidine PNPs that are indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors and degraders, termed iDegs. Structural fine-tuning modulated both degradation and inhibition potencies. Co-crystallization revealed that iDegs induce unprecedented changes in the C-terminus of IDO1 which promote degradation. iDegs inhibited tumor growth in SKOV-3 tumor-bearing mice and led to prolonged survival, which promises to inspire novel medicinal chemistry programs aimed at IDO1 in different diseases.
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Registered trials
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