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

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that metabolizes tryptophan, and its activity can lead to immunosuppression, thereby allowing tumors to evade the immune system. IDO1 can also suppress the immune response through mechanisms independent of its enzyme activity, and this MoA may be difficult to target with current inhibitors. Drugs targeting only IDO1 enzyme activity have failed to improve the overall survival of patients with cancer. Developing new therapeutics that neutralize both enzyme- and non-enzyme-derived immunosuppressive IDO1 effects is therefore of high interest.
 

WuXi AppTec scientists contributed to a publication in the Journal of Medicinal Chemistry that built upon previous work identifying a novel proteolysis-targeting chimera (PROTAC), NU223612, which degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in brain tumors.
 

In this study, the authors rationally optimized the structure of their lead series to create NU227326. 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 cancers.

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