Rational Design and Optimization of a Potent IDO1 Proteolysis Targeting Chimera (PROTAC)

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, in vivo. In this study, we rationally optimized the structure of our lead
series to create NU227326, which degrades IDO1 with a DC50 of 5 nM in human GBM cells. Mechanistic studies showed that IDO1
degradation occurred through the ubiquitin–proteasome system
and was sustained for at least 2 days, supporting NU227326 as a highly
potent IDO1 PROTAC suitable for further studies in GBM and other human
cancers.