{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Monsen PJ"],"funding":["National Institute of Neurological Disorders and Stroke","American Cancer Society","Division of Electrical, Communications and Cyber Systems","NIA NIH HHS","NIH Office of the Director","GBM Foundation","National Cancer Institute","NCI NIH HHS","NINDS NIH HHS","National Institute on Aging","NIH HHS"],"pagination":["4961-4987"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11874035"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["68(4)"],"pubmed_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, <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"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)."],"pmcid":["PMC11874035"],"funding_grant_id":["R01 CA218278","R01NS129835","R00 NS082381","ECCS-2025633","R37 CA279341","R01CA218278","K99 NS082381","R01 NS129835","S10OD023681","RSG-21-058-01 - CCE","R01 CA214608","R01 NS097851","F32 NS073366","K02 AG068617","S10 OD023681","P30 CA060553","K02AG068617","R01NS097851","R01CA214608","P30CA060553"],"pubmed_authors":["Zhang F","Jiang H","Ojo O","Monsen PJ","Lauing KL","Zhai L","Koch T","Mao Y","Fanning SW","Yamini B","Wainwright DA","Sanchez-Gomez P","Allen JM","Lukas RV","Dunne SF","Berardi P","Schiltz GE","Grigorescu AA","Song G","Egozi M","Kregel S","Jha S","Vaziri-Gohar A","Penco-Campillo M","Bommi PV"],"additional_accession":[]},"is_claimable":false,"name":"Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC).","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, <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","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Feb","modification":"2026-06-01T22:06:40.569Z","creation":"2025-04-04T13:46:47.771Z"},"accession":"S-EPMC11874035","cross_references":{"pubmed":["39946350"],"doi":["10.1021/acs.jmedchem.5c00026"]}}