Biological Sciences Division
Published February 13, 2025 | Version v1
Journal article Open

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

Creators

  • 1. Northwestern University
  • 2. Loyola University Chicago
  • 3. HD Biosciences (China) Co., Ltd.
  • 4. Unidad Funcional de Investigación en Enfermedades Crónicas
  • 5. University of Chicago

Description

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Files

monsen-et-al-2025-rational-design-and-optimization-of-a-potent-ido1-proteolysis-targeting-chimera-(protac).pdf

Files (18.0 MB)

Name Size Download all
Supporting information
md5:596cf43e33a0ae789f77b74c07fa7cd3
4.3 MB Preview Download
Article
md5:7b3241b9329e88474a7c56214e8533f1
13.7 MB Preview Download

Additional details

Identifiers

DOI
10.1021/acs.jmedchem.5c00026
Other
oai:uchicago.tind.io:14604

Funding

National Institutes of Health
R01NS097851
National Institutes of Health
K02AG068617
National Institutes of Health
R01NS129835
American Cancer
Scholar Research Scholar Award
GBM Foundation
National Institutes of Health
S10OD023681
National Science Foundation
ECCS-2025633
State of Illinois
International Institute for Nanotechnology
Northwestern University
National Cancer Institute
P30CA060553
National Institutes of Health
CA214608
National Institutes of Health
CA218278

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Neurological Surgery