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 this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874035 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.5c00026 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The aryl hydrocarbon receptor controls IFN-γ-induced immune checkpoints PD-L1 and IDO via the JAK/STAT pathway in lung adenocarcinoma.
J Immunol
March 2025
Department of Environmental Health, Boston University School of Public Health, Boston, MA, United States.
While immunotherapy has shown some efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation, the AhR, a known but counterintuitive mediator of immunosuppression (interferon (IFN)-γ), and regulation of two immune checkpoints (PD-L1 and IDO).
View Article and Find Full Text PDFRadiation-Enhanced AF1q Moves Center Stage as a Key Driver to Favorable Tumor Stage in Rectal Cancer Patients.
Cancer Med
March 2025
Department of Experimental and Animal Pathology, Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria.
Background: Enhanced protein expression of ALL1-fused gene from chromosome 1q (AF1Q) after (chemo)radiotherapy has been described in vitro, but is largely understudied in gastrointestinal cancer. We aimed to investigate AF1q expression in rectal cancer (RC) patients treated with short-term radiation therapy and a possible correlation with markers crucial for RC prognosis.
Methods: A cohort of 75 RC patients scheduled for surgery was defined and patients with moderately locally advanced tumors (cT3Nx) received preoperative hyperfractionated short-term radiation therapy (cumulative dose 25 Gy).
Prognostic significance of the inhibitory-to-stimulatory immune checkpoint ratio in patients with breast cancer.
Front Oncol
February 2025
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Shandong, China.
Background: Accumulating evidences suggested that immune checkpoints (ICPs) played an important role in malignancies including breast cancer (BRCA). We aimed to investigate whether inhibitory-to-stimulatory immune checkpoint ratio (ISICPR) could be used as a prognostic marker for BRCA.
Methods: BRCA patients were enrolled from The Cancer Genome Atlas (TCGA).
IDO1 inhibition enhances CLDN18.2-CAR-T cell therapy in gastrointestinal cancers by overcoming kynurenine-mediated metabolic suppression in the tumor microenvironment.
J Transl Med
March 2025
Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Background: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies but faces significant limitations in gastrointestinal tumors due to the immunosuppressive tumor microenvironment (TME). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the TME, suppresses T cell efficacy by catalyzing tryptophan degradation to kynurenine (Kyn), leading to T cell exhaustion and reduced cytotoxicity. This study investigates the role of IDO1 inhibition in overcoming metabolic suppression by kynurenine and enhancing Claudin18.
View Article and Find Full Text PDFDiscovery and Optimization of Novel Apo-IDO1 Inhibitors by a Pharmacophore-Based Structural Simplification Strategy.
J Med Chem
March 2025
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, P. R. China.
Indoleamine 2,3-dioxygenase-1 (IDO1) plays a crucial role in tumor immune escape. However, the limited clinical efficacy of traditional IDO1 inhibitors has impeded their further development. Recently, apo-IDO1 inhibitors that displace the heme to target IDO1 have been discovered, which exhibits a slow dissociation rate reminiscent of irreversible inhibitors.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!