Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders
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.
Authors
- Stefano Ugel (ORCID: https://orcid.org/0000-0002-6639-7608)
- Matthias Bischoff (ORCID: https://orcid.org/0009-0002-4046-7580)
- Sonja Sievers (ORCID: https://orcid.org/0000-0003-0854-4507)
- Anke Unger (ORCID: https://orcid.org/0000-0003-1288-3763)
- Belén Lucas (ORCID: https://orcid.org/0009-0008-1426-5815)
- Philipp Lampe
- Annika Schmidt (ORCID: https://orcid.org/0000-0002-7189-0800)
- Carsten Strohmann (ORCID: https://orcid.org/0000-0002-4787-2135)
- Soheila Rezaei Adariani (ORCID: https://orcid.org/0000-0002-0344-3232)
- Herbert Waldmann (ORCID: https://orcid.org/0000-0002-9606-7247)
- Suyuan Chen (ORCID: https://orcid.org/0000-0003-0972-936X)
- Vincenzo Bronte (ORCID: https://orcid.org/0000-0002-3741-5141)
- Kamal Kumar (ORCID: https://orcid.org/0000-0003-3593-8421)
- Slava Ziegler (ORCID: https://orcid.org/0000-0003-4398-7741)
- Malte Gersch (ORCID: https://orcid.org/0000-0003-2767-9589)
- Raphael Gasper (ORCID: https://orcid.org/0000-0002-7780-0773)
- Petra Janning
- Kesava Reddy Naredla
- María Ortiz Lucas
- Xiu‐Fen Cheng
Institutions
- University of Verona (IT)
- TU Dortmund University (DE)
- Instituto de Biomedicina y Biotecnología de Cantabria (ES)
- Lead Discovery Center (Germany) (DE)
- Max Planck Institute of Molecular Physiology (DE)
- Chemical Genomics Centre (DE)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1002/anie.202518753
- Citations
- 1
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.58
Funders
- European Federation of Pharmaceutical Industries and Associations
- European Commission
- European Synchrotron Radiation Facility
- Max-Planck-Gesellschaft
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Italiana per la Ricerca sul Cancro
- Agencia Estatal de Investigación