2. Academic Validation
  3. Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)

Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)

  • J Med Chem. 2025 Feb 27;68(4):4961-4987. doi: 10.1021/acs.jmedchem.5c00026.
Paige J Monsen 1,  Prashant V Bommi 2,  Arabela A Grigorescu 3,  Kristen L Lauing 2,  Yingyu Mao 4,  Payton Berardi 2,  Lijie Zhai 2,  Oluwatomilayo Ojo 2,  Manon Penco-Campillo 2,  Taylor Koch 2,  Michael Egozi 2,  Sonam Jha 1,  Sara F Dunne 4,  Hong Jiang 5,  Guiqin Song 5,  Fang Zhang 5,  Steven Kregel 2 6,  Ali Vaziri-Gohar 2 6 7,  Sean W Fanning 2,  Pilar Sanchez-Gomez 8,  Jacob M Allen 9,  Bakhtiar Yamini 10,  Rimas V Lukas 11,  Derek A Wainwright 2 6 12,  Gary E Schiltz 1 13 14
Affiliations

Affiliations

  • 1 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
  • 2 Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, United States.
  • 3 Department of Molecular Biosciences, Northwestern University Weinberg College of Arts and Sciences, Evanston, Illinois 60208, United States.
  • 4 High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208, United States.
  • 5 HD Biosciences (China) Co., Ltd., A WuXi AppTec Company, Shanghai 201201, China.
  • 6 Cardinal Bernardin Cancer Center, Maywood, Illinois 60153, United States.
  • 7 Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, United States.
  • 8 Neuro-Oncology Unit, Unidad Funcional de Investigación en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain.
  • 9 Department of Health and Kinesiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • 10 Department of Neurological Surgery, University of Chicago Medicine, Chicago, Illinois 60637, United States.
  • 11 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 12 Department of Neurological Surgery, Loyola University Medical Center, Maywood, Illinois 60153, United States.
  • 13 Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States.
  • 14 Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611 United States.
PMID: 39946350 DOI: 10.1021/acs.jmedchem.5c00026
Abstract

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, in vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC50 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.

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