Targeted Degradation of Indoleamine 2,3-Dioxygenase 1 Using PROTAC Technology

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the first and 
rate-limiting step in the oxidative metabolism of tryptophan along the kynurenine pathway. 
Aberrant activation of this pathway is strongly associated with tumor immune suppression. 
Overexpression of IDO1 in tumor cells and antigen-presenting cells results in local depletion of 
tryptophan and accumulation of immunomodulatory metabolites such as kynurenine. These 
metabolic changes inhibit effector T-cell proliferation and promote the differentiation of regulatory 
T cells, thereby contributing to an immunosuppressive tumor microenvironment. Considerable 
medicinal chemistry efforts have focused on developing small-molecule inhibitors that block the 
catalytic activity of IDO1, including compounds such as epacadostat. Although these inhibitors 
effectively suppress enzymatic activity, they do not remove the IDO1 protein from cells and 
therefore may not fully address additional biological functions of the enzyme. Emerging evidence 
indicates that IDO1 can also exert non-enzymatic signaling functions that contribute to immune 
regulation, suggesting that catalytic inhibition alone may be insufficient to fully modulate IDO1 
biology. Proteolysis targeting chimeras (PROTACs) provide an alternative strategy for modulating 
protein function through targeted degradation. PROTAC molecules are heterobifunctional 
compounds consisting of a ligand that binds the target protein and a second ligand that recruits an 
E3 ubiquitin ligase. Formation of a ternary complex between the target protein and the E3 ligase 
promotes ubiquitination and subsequent degradation of the target protein by the ubiquitin–
proteasome system. Application of this strategy to IDO1 has enabled the development of the first 
potent PROTAC degrader capable of inducing efficient and sustained degradation of the enzyme 
in cancer cells, achieving up to 93% reduction of cellular IDO1 protein levels. These findings 
demonstrate that targeted protein degradation represents a promising strategy for modulating 
immunoregulatory enzymes such as IDO1