9S1V

Crystal structure of human IDO1 in complex with iDeg-6

This is a non-PDB format compatible entry.

Summary for 9S1V

• Entry DOI: 10.2210/pdb9s1v/pdb
• Descriptor: Indoleamine 2,3-dioxygenase 1, DI(HYDROXYETHYL)ETHER, [(1~{R},2~{S},6~{S},8~{R})-4-(4-~{tert}-butyl-2-methyl-phenyl)sulfonyl-9,9-dimethyl-4-azatricyclo[6.1.1.0^{2,6}]decan-2-yl]methyl ~{N}-(4-ethynylphenyl)carbamate, ... (5 entities in total)
• Functional Keywords: ido1, heme-binding protein, pseudo-natural product, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 46546.78

Authors

Lucas, B.,Cheng, X.,Lucas, M.,Ziegler, S.,Waldmann, H.,Gasper, R. (deposition date: 2025-07-21, release date: 2025-12-10)

Primary citation

Cheng, X.F.,Lucas, B.,Lampe, P.,Ugel, S.,Chen, S.,Unger, A.,Bischoff, M.,Adariani, S.R.,Naredla, K.R.,Kumar, K.,Schmidt, A.,Strohmann, C.,Janning, P.,Gasper, R.,Lucas, M.,Gersch, M.,Sievers, S.,Bronte, V.,Ziegler, S.,Waldmann, H.
Design, Synthesis, and Structural Evolution of Pseudo-Natural Product IDO1 Inhibitors and Degraders.
Angew.Chem.Int.Ed.Engl., :e18753-e18753, 2025

PubMed 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.

PubMed: 41310997
DOI: 10.1002/anie.202518753

Experimental method

X-RAY DIFFRACTION (1.85 Å)