Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders
Abstract
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.
Article Details
Authors (20)
Xiu‐Fen Cheng
Abteilung Chemische Biologie Max‐Planck‐Institut für Molekulare Physiologie Otto‐Hahn‐Straße 11 44227 Dortmund Germany
Belén Lucas
Abteilung Chemische Biologie Max‐Planck‐Institut für Molekulare Physiologie Otto‐Hahn‐Straße 11 44227 Dortmund Germany
Philipp Lampe
Compound Management and Screening Center Otto‐Hahn‐Straße 15 44227 Dortmund Germany
Stefano Ugel
Immunology Section Department of Medicine, University and Hospital Trust (AOUI) of Verona P.le L.A. Scuro, 10 Verona 37134 Italy
Suyuan Chen
Department of Chemical Biology
Anke Unger
Matthias Bischoff
Compound Management and Screening Center Otto‐Hahn‐Straße 15 44227 Dortmund Germany
Soheila Rezaei Adariani
Abteilung Chemische Biologie Max‐Planck‐Institut für Molekulare Physiologie Otto‐Hahn‐Straße 11 44227 Dortmund Germany
Kesava Reddy Naredla
Abteilung Chemische Biologie Max‐Planck‐Institut für Molekulare Physiologie Otto‐Hahn‐Straße 11 44227 Dortmund Germany
Kamal Kumar
Annika Schmidt
Carsten Strohmann
Fakultät Chemie und Chemische Biologie Technische Universität Dortmund Otto‐Hahn‐Straße 6 44221 Dortmund Germany
Petra Janning
Raphael Gasper
Maria Lucas
Malte Gersch
Sonja Sievers
Compound Management and Screening Center Otto‐Hahn‐Straße 15 44227 Dortmund Germany
Vincenzo Bronte
Immunology Section Department of Medicine, University and Hospital Trust (AOUI) of Verona P.le L.A. Scuro, 10 Verona 37134 Italy
Slava Ziegler
Abteilung Chemische Biologie Max‐Planck‐Institut für Molekulare Physiologie Otto‐Hahn‐Straße 11 44227 Dortmund Germany
Herbert Waldmann