Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and nonenzymatic functions. Drugs targeting IDO1 enzyme activity have failed to improve the overall survival of patients with cancer. Developing new therapeutics that neutralize both enzyme- and nonenzyme-derived immunosuppressive IDO1 effects is therefore of high interest. We previously described a novel proteolysis targeting chimera (PROTAC), NU223612, that degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in well-established brain tumors, <i>in vivo</i>. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC<sub>50</sub> of 5 nM in human GBM cells. Mechanistic studies showed that IDO1 degradation occurred through the ubiquitin-proteasome system and was sustained for at least 2 days, supporting NU227326 as a highly potent IDO1 PROTAC suitable for further studies in GBM and other human cancers.
Authors
- Sara F. Dunne (ORCID: https://orcid.org/0000-0002-0273-680X)
- Jacob M. Allen (ORCID: https://orcid.org/0000-0001-9476-7605)
- Kristen L. Lauing (ORCID: https://orcid.org/0000-0002-4408-1821)
- Hong Jiang (ORCID: https://orcid.org/0000-0002-3745-5549)
- Manon Penco-Campillo (ORCID: https://orcid.org/0000-0002-9438-6041)
- Sean William Fanning (ORCID: https://orcid.org/0000-0002-9428-0060)
- Ali Vaziri‐Gohar (ORCID: https://orcid.org/0000-0002-6924-8691)
- Ohiowele Ojo
- Arabela A. Grigorescu (ORCID: https://orcid.org/0000-0003-0429-8994)
- Prashant Bommi (ORCID: https://orcid.org/0000-0002-9457-1730)
- Paige J. Monsen
- Zhang Fei (ORCID: https://orcid.org/0000-0002-1194-8513)
- Sonam Jha (ORCID: https://orcid.org/0000-0002-5118-3244)
- Pilar Sánchez‐Gómez (ORCID: https://orcid.org/0000-0002-0709-4973)
- Gary E. Schiltz (ORCID: https://orcid.org/0000-0003-4180-5051)
- Yingyu Mao (ORCID: https://orcid.org/0000-0001-5182-7401)
- Derek A. Wainwright (ORCID: https://orcid.org/0000-0001-7232-4264)
- Bakhtiar Yamini
- P Berardi
- Guiqin Song (ORCID: https://orcid.org/0000-0002-8068-4742)
- Rimas V. Lukas (ORCID: https://orcid.org/0000-0002-9352-5396)
- Steven Kregel
- Lijie Zhai
- Tad H. Koch
- Michael Egozi
Institutions
- Northwestern University (US)
- Loyola University Medical Center (US)
- University of Illinois Urbana-Champaign (US)
- Loyola University Chicago (US)
- WuXi AppTec (China) (CN)
- Cardinal Health (Australia) (AU)
- Instituto de Salud Carlos III (ES)
- University of Chicago (US)
- Indo-American Center (US)
- Northwestern University (PH)
- Unidad Funcional de Investigación de Enfermedades Crónicas (ES)
- High Throughput Biology (United States) (US)
- Neurological Surgery (US)
- Bernard (Czechia) (CZ)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00026
- Citations
- 16
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 12.90
Funders
- American Cancer Society
- National Institute on Aging
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Division of Electrical, Communications and Cyber Systems