2. Academic Validation
  3. Identification of a Monovalent Pseudo-Natural Product Degrader Class Supercharging Degradation of IDO1 by its native E3 KLHDC3

Identification of a Monovalent Pseudo-Natural Product Degrader Class Supercharging Degradation of IDO1 by its native E3 KLHDC3

  • bioRxiv. 2025 Jan 17:2024.07.10.602857. doi: 10.1101/2024.07.10.602857.
Elisabeth Hennes 1 2,  Belén Lucas 1,  Natalie S Scholes 3,  Xiu-Fen Cheng 1,  Daniel C Scott 4,  Matthias Bischoff 5,  Katharina Reich 1,  Raphael Gasper 6,  María Lucas 7,  Teng Teng Xu 8,  Lisa-Marie Pulvermacher 1,  Lara Dötsch 1 2,  Hana Imrichova 3,  Alexandra Brause 1,  Kesava Reddy Naredla 1,  Sonja Sievers 5,  Kamal Kumar 1,  Petra Janning 1,  Malte Gersch 2 9,  Peter J Murray 8,  Brenda A Schulman 4 10,  Georg E Winter 3,  Slava Ziegler 1,  Herbert Waldmann 1 2
Affiliations

Affiliations

  • 1 Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
  • 2 Technische Universität Dortmund, Fakultät Chemie und Chemische Biologie, Otto-Hahn-Straße 6, 44221 Dortmund, Germany.
  • 3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 4 Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5 Compound Management and Screening Center Otto-Hahn-Str.11, 44227 Dortmund, Germany.
  • 6 Max-Planck-Institut für Molekulare Physiologie, Zentrale Einheit für Kristallographie und Biophysik, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.
  • 7 Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC, C/Albert Einstein 22, PCTCAN, 39011 Santander, Spain.
  • 8 Immunoregulation Research Group, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 9 Chemical Genomics Centre, Max-Planck-Institut für Molekulare Physiologie, 44227 Dortmund, Germany.
  • 10 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
PMID: 39026748 DOI: 10.1101/2024.07.10.602857
Abstract

Targeted protein degradation (TPD) modulates protein function beyond inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating proximity between a neosubstrate and hijacked E3 Ligase. Here, we identified pseudo-natural products derived from (-)-myrtanol, termed iDegs that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 Ligase CRL2KLHDC3, which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce formation of kynurenine by both inhibition and induced degradation of the enzyme and, thus, would also modulate non-enzymatic functions of IDO1. This unique mechanism of action may open up new therapeutic opportunities for the treatment of Cancer beyond classical inhibition of IDO1.

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