2. Academic Validation
  3. Design, Synthesis, and Structural Evolution of Pseudo-Natural Product IDO1 Inhibitors and Degraders

Design, Synthesis, and Structural Evolution of Pseudo-Natural Product IDO1 Inhibitors and Degraders

  • Angew Chem Int Ed Engl. 2026 Jan 16;65(3):e18753. doi: 10.1002/anie.202518753.
Xiu-Fen Cheng 1,  Belén Lucas 1,  Philipp Lampe 2,  Stefano Ugel 3,  Suyuan Chen 1,  Anke Unger 4,  Matthias Bischoff 2,  Soheila Rezaei Adariani 1,  Kesava Reddy Naredla 1,  Kamal Kumar 1,  Annika Schmidt 5,  Carsten Strohmann 5,  Petra Janning 1,  Raphael Gasper 1,  María Lucas 6,  Malte Gersch 5 7,  Sonja Sievers 2,  Vincenzo Bronte 3,  Slava Ziegler 1,  Herbert Waldmann 1 5
Affiliations

Affiliations

  • 1 Abteilung Chemische Biologie, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.
  • 2 Compound Management and Screening Center, Otto-Hahn-Straße 15, 44227, Dortmund, Germany.
  • 3 Immunology Section, Department of Medicine, University and Hospital Trust (AOUI) of Verona, P.le L.A. Scuro, 10, Verona, 37134, Italy.
  • 4 Lead Discovery Center GmbH (LDC), Otto-Hahn- Straße 15, 44227, Dortmund, Germany.
  • 5 Fakultät Chemie und Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44221, Dortmund, Germany.
  • 6 Instituto de Biomedicina y Biotecnología de Cantabria IBBTEC, Universidad de Cantabria-CSIC, C/ Albert Einstein 22, PCTCAN, Santander, 39011, Spain.
  • 7 Chemical Genomics Center, Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn- Straße 15, 44227, Dortmund, Germany.
PMID: 41310997 DOI: 10.1002/anie.202518753
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.

Keywords

Bicyclic monoterpenes; Biophysical characterization; Co‐crystallization insights; IDO1 inhibitors and Degraders; Pyrrolidine alkaloid.

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