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

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.