2. Academic Validation
  3. Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

  • J Med Chem. 2022 Nov 21. doi: 10.1021/acs.jmedchem.2c00771.
Lakshmi R Bollu 1,  Prashant V Bommi 1,  Paige J Monsen 2,  Lijie Zhai 1,  Kristen L Lauing 1,  April Bell 1,  Miri Kim 3,  Erik Ladomersky 1,  Xinyu Yang 4,  Leonidas C Platanias 5 6,  Daniela E Matei 6 7,  Marcelo G Bonini 5 6,  Hidayatullah G Munshi 5 6,  Rintaro Hashizume 6 8,  Jennifer D Wu 6 9 10,  Bin Zhang 5 10,  Charles David James 1,  Peiwen Chen 1,  Masha Kocherginsky 6 7 11,  Craig Horbinski 1 6 12,  Michael D Cameron 13,  Arabela A Grigorescu 14,  Bakhtiar Yamini 15,  Rimas V Lukas 6 16,  Gary E Schiltz 2 6 17,  Derek A Wainwright 1 5 6 10
Affiliations

Affiliations

  • 1 Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 2 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
  • 3 Department of Neurological Surgery, Loyola University Medical Center, Maywood, Illinois 60153, United States.
  • 4 WuXi AppTec, Shanghai 200131, People's Republic of China.
  • 5 Department of Medicine─Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 6 Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, United States.
  • 7 Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 8 Department of Pediatrics - Division of Hematology, Oncology, and Stem Cell Transplantation, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 9 Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 10 Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 11 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 12 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 13 Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.
  • 14 Department of Molecular Biosciences, Northwestern University Weinberg College of Arts and Sciences, Evanston, Illinois 60208, United States.
  • 15 Department of Neurological Surgery, Division of the Biological Sciences, The University of Chicago, Chicago, Illinois 60637, United States.
  • 16 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • 17 Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
PMID: 36410047 DOI: 10.1021/acs.jmedchem.2c00771
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive Enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with Cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 Enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 Enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

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