Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype

• Published in: Angewandte Chemie International Edition 2022-10, Vol.61 (40), p.e202209374-n/a
• Main Authors: Davies, Caitlin, Dötsch, Lara, Ciulla, Maria Gessica, Hennes, Elisabeth, Yoshida, Kei, Gasper, Raphael, Scheel, Rebecca, Sievers, Sonja, Strohmann, Carsten, Kumar, Kamal, Ziegler, Slava, Waldmann, Herbert
• Format: Article
• Language: English
• Subjects: Amino Acids; Autoimmunity; Bioactive compounds; Biological Products - chemistry; Biological Products - pharmacology; Cancer; Chemical reactions; Crystal structure; Dioxygenase; Enantiomers; Enzyme Inhibitors - chemistry; Fragments; Heme; Heme Proteins; Immunology; Indoleamine-Pyrrole 2,3,-Dioxygenase; Indoles; Inhibitors; Natural Products; Neural networks; Neurodegeneration; Pyrrolidines; Structural analysis; Structure-Activity Relationship; Structure-Activity Relationships
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202209374

Natural product (NP)‐inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo‐natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo‐NP class, whereby indole‐ and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3‐dioxygenase 1 (IDO1), a heme‐containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo‐IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo‐IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research. Pseudo‐natural products are de novo combinations of natural product (NP) fragments to target biologically relevant chemical space not covered by existing NPs. We describe the design and synthesis of the novel pseudo‐NP class termed apoxidoles. Biological investigation revealed potent reduction of cellular kynurenine levels by apoxidoles through selective targeting of apo‐indoleamine 2,3‐dioxygenase 1 (apo‐IDO1).