Indoleamine 2,3-dioxygenase 1 (IDO1; IDO) is an immunosuppressive factor that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To-date, most IDO-targeted therapies 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 IDO protein. IDO-PROTACs were tested for their effects on IDO enzyme and non-enzyme activities. After screening a library of IDO-PROTAC derivatives, a compound was identified that potently degraded IDO protein through cereblon-mediated proteasomal degradation. The IDO-PROTAC: (i) inhibited IDO enzyme activity and IDO-mediated NF-kB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded IDO 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 IDO protein degrader with therapeutic potential for patients with glioblastoma.
Bollu, Lakshmi and Bommi, Prashant V. and Monsen, Paige J. and Zhai, Lijie and Lauing, Kristen L. and Bell, April and Kim, Miri and Ladomersky, Erik and Platanias, Leonidas C. and Matei, Daniela E. and Bonini, Marcelo G. and Munshi, Hidayatullah G. and Hashizume, Rintaro and Wu, Jennifer D. and Zhang, Bin and James, C. David and Chen, Peiwen and Kocherginsky, Masha and Horbinski, Craig and Cameron, Michael D. and Grigorescu, Arabela A. and Yamini, Bakhtiar and Lukas, Rimas V. and Schiltz, Gary E. and Wainwright, Derek Alan, Identification and Characterization of a Novel Brain-Penetrant Indoleamine 2,3 Dioxygenase 1 Protein Degrader for Glioblastoma. Available at SSRN: https://ssrn.com/abstract=4081515 or http://dx.doi.org/10.2139/ssrn.4081515
This version of the paper has not been formally peer reviewed.
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