Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders
Year: 2025
Type: article
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.
Authors: Xiu‐Fen Cheng, Belén Lucas, Philipp Lampe, Stefano Ugel, Suyuan Chen, Anke Unger, Matthias Bischoff, Soheila Rezaei Adariani, Kesava Reddy Naredla, Kamal Kumar, Annika Schmidt, Carsten Strohmann, Petra Janning, Raphael Gasper, María Lucas, Malte Gersch, Sonja Sievers, Vincenzo Bronte, Slava Ziegler, Herbert Waldmann
Institutions: Max Planck Institute of Molecular Physiology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Lead Discovery Center (Germany), TU Dortmund University, Universidad de Cantabria, Consejo Superior de Investigaciones Científicas, Instituto de Biomedicina y Biotecnología de Cantabria, Chemical Genomics Centre
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,510
Awards: G1073258374, G1175115578, G210041235, G2262748287, G2601397997, G300979063, G3207356259, G34346518, European Lead Factory, G3480869486, G3681454997, G393177772, G4042783231, G4072214037, G425668148, G4442677895, G4526231891, G504309314, G5080475149, G5195188938, G5315675380, G544149491, G5702163051, G6956238669, G7084143925, G7244591491, G7434936867, G7919341541
OpenAlex ID: W4416774920