Monovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3
Targeted protein degradation modulates protein function beyond the inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating the proximity between a neosubstrate and a hijacked E3 ligase. Here we identify 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 CRL2<sup>KLHDC3</sup>, 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 the formation of kynurenine by both inhibition and induced degradation of the enzyme and thus also modulate the non-enzymatic functions of IDO1. This unique mechanism of action may open up alternative therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.
Authors
- Matthias Bischoff (ORCID: https://orcid.org/0009-0002-4046-7580)
- Sofia Rossini (ORCID: https://orcid.org/0000-0001-6429-9425)
- Sonja Sievers (ORCID: https://orcid.org/0000-0003-0854-4507)
- Brenda Arlene Schulman (ORCID: https://orcid.org/0000-0002-3083-1126)
- Daniel C. Scott (ORCID: https://orcid.org/0000-0002-7688-5568)
- Belén Lucas (ORCID: https://orcid.org/0009-0008-1426-5815)
- Alexandra Brause
- Herbert Waldmann (ORCID: https://orcid.org/0000-0002-9606-7247)
- Lara Dötsch (ORCID: https://orcid.org/0000-0001-8100-5636)
- Hana Imrichová (ORCID: https://orcid.org/0000-0003-0385-1823)
- Slava Ziegler (ORCID: https://orcid.org/0000-0003-4398-7741)
- Natalie S. Scholes (ORCID: https://orcid.org/0000-0002-1053-4079)
- Siska Führer (ORCID: https://orcid.org/0009-0000-4334-221X)
- Malte Gersch (ORCID: https://orcid.org/0000-0003-2767-9589)
- Petra Janning
- Kesava Reddy Naredla
- Matthew C. Lucas (ORCID: https://orcid.org/0009-0000-9140-3806)
- Teng Teng Xu
- Xiu-Fen Cheng
- Raphael Gasper
- Georg E. Winter
- Lisa-Marie Pulvermacher
- Elisabeth Hennes
- Kamal Kumar
- Katharina Reich
- Ciriana Orabona
- Peter J. Murray
Institutions
- St. Jude Children's Research Hospital (US)
- Universidad de Cantabria (ES)
- Austrian Academy of Sciences (AT)
- Max Planck Society (DE)
- TU Dortmund University (DE)
- University of Perugia (IT)
- Instituto de Biomedicina y Biotecnología de Cantabria (ES)
- CeMM Research Center for Molecular Medicine (AT)
- Max Planck Institute of Molecular Physiology (DE)
- Max Planck Institute of Biochemistry (DE)
- Chemical Genomics Centre (DE)
- Voith (United States) (US)
Publication Details
- Journal
- Nature Chemistry
- Published
- 2026-01-07
- DOI
- https://doi.org/10.1038/s41557-025-02021-5
- Citations
- 1
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 27.61