TY - JOUR
T1 - Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma
AU - Bollu, Lakshmi R.
AU - Bommi, Prashant V.
AU - Monsen, Paige J.
AU - Zhai, Lijie
AU - Lauing, Kristen L.
AU - Bell, April
AU - Kim, Miri
AU - Ladomersky, Erik
AU - Yang, Xinyu
AU - Platanias, Leonidas C
AU - Matei, Daniela Elena
AU - Bonini, Marcelo G.
AU - Munshi, Hidayatullah G
AU - Hashizume, Rintaro
AU - Wu, Jennifer D.
AU - Zhang, Bin
AU - James, Charles David
AU - Chen, Peiwen
AU - Kocherginsky, Maria Nikolai
AU - Horbinski, Craig Michael
AU - Cameron, Michael D.
AU - Grigorescu, Arabela A.
AU - Yamini, Bakhtiar
AU - Lukas, Rimas Vincas
AU - Schiltz, Gary E
AU - Wainwright, Derek Alan
N1 - Funding Information:
We thank and acknowledge WuXi AppTec (China) for technical assistance with compound synthesis. This work was supported in part by the National Institutes of Health (NIH) grants R01NS113425 (L.C.P.), R01NS102669 (C.H.), P50CA221747 (L.C.P., R.V.L., C.H., C.D.J., and D.A.W.), R01NS097851 (D.A.W. and G.E.S.), K02AG068617 (D.A.W.), BrainUp grant 2136 (R.V.L. and D.A.W.), Lou Malnati Brain Tumor Institute (R.V.L., G.E.S., and D.A.W.), American Cancer Scholar Research Scholar Award RSG-21-058-01 - CCE (D.A.W.), the GBM Foundation (D.A.W.), 5 for the Fight (D.A.W.), and the Chicago Biomedical Consortium Director’s Fund Award DF-008 (G.E.S., D.A.W.).
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/12/8
Y1 - 2022/12/8
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.2c00771
DO - 10.1021/acs.jmedchem.2c00771
M3 - Article
C2 - 36410047
AN - SCOPUS:85142512036
SN - 0022-2623
VL - 65
SP - 15642
EP - 15662
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -
