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

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.

• Authors: Lakshmi R Bollu, Prashant V Bommi, Paige J Monsen, Lijie Zhai, Kristen L Lauing, April Bell, Miri Kim, Erik Ladomersky, Xinyu Yang, Leonidas C Platanias, Daniela E Matei, Marcelo G Bonini, Hidayatullah G Munshi, Rintaro Hashizume, Jennifer D Wu, Bin Zhang, Charles David James, Peiwen Chen, Masha Kocherginsky, Craig Horbinski, Michael D Cameron, Arabela A Grigorescu, Bakhtiar Yamini, Rimas V Lukas, Gary E Schiltz, Derek A Wainwright
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 23 Pg. 15642-15662 (12 08 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 36410047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Tryptophan
• Proteolysis Targeting Chimera

Topics

• Humans
• Animals
• Mice
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Tryptophan
• Proteolysis Targeting Chimera
• Brain Neoplasms (drug therapy)