epacadostat (INCB024360)

Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC.

P2, N=33, Not yet recruiting, Changhai Hospital

P2, N=10, Not yet recruiting, Tianjin Third Central Hospital; Tianjin Third Central Hospital

P3, N=89, Completed, Incyte Corporation | Active, not recruiting --> Completed

P2, N=51, Completed, Washington University School of Medicine | Active, not recruiting --> Completed | Trial completion date: Apr 2026 --> Oct 2025

By studying the turnover of IDO1 protein in human tumor cells exposed to various IDO1 catalytic inhibitors, such as epacadostat, linrodostat, and navoximod, we show here that these molecules stabilize a non-enzymatic protein conformation of IDO1, independently of their mechanism of inhibition. In the thyroid carcinoma cell line FTC-133, the stabilized and non-enzymatic IDO1 protein promotes the proliferation and migration of the tumor, resulting in an adverse pro-tumorigenic effect. These results uncover an unexpected adverse effect of IDO1 inhibitors in the tumor microenvironment that overcomes the enzymatic inhibition of IDO1, and suggest protein degradation, rather than enzymatic inhibition, as a more effective approach to target IDO1 in the tumor microenvironment.

CAFs suppressed T-cell proliferation and induced PD-1 expression in CD4+ and CD8+ T cells, effects reversed by epacadostat. IDO1 inhibition enhanced T-cell proliferation via AKT signaling, restored T-cell cytotoxicity, and increased ovarian cancer cell apoptosis. These findings suggest that targeting IDO1 may help counteract CAF-mediated immunosuppression and enhance antitumor immunity in HGSOC.

Among these, medications like Indoximod, Epacadostat, and Navoximod have shown promise in influencing the immune system and slowing tumor progression, while dual inhibitors like HTI-1090 try to address broader metabolic connections. The use of IDO/TDO inhibitors with conventional anticancer medications demonstrates their potential to reshape cancer treatment paradigms, contingent on further research to optimize efficacy and safety. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT03844438.

In vivo, a subcutaneous xenograft tumor model of nude mice was established by subcutaneously inoculating SK-HEP1 and treated with IDO1 catalytic inhibitor epacadostat (EPA) to observe the effect of IDO1 on tumor growth and immune cells infiltration...Targeting IDO1 may represent a promising immunotherapeutic strategy. However, its immunomodulatory effects must be validated in immunocompetent or humanized animal systems before clinical translation.

A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme's catalytic function, all three catalytic inhibitors modulate the IDO1's signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells.

The therapeutic landscape of IDO1 inhibition has progressed significantly from early heme-competitive inhibitors like epacadostat to next-generation proteolysis-targeting chimera (PROTAC) technology...This review systematically evaluates: (1) clinically investigated IDO1 inhibitors and their pharmacological profiles, and (2) the preclinical promise of IDO1-targeting PROTAC degraders. Through critical analysis of their mechanisms of action and therapeutic potential, we provide insights into optimizing IDO1-targeted strategies for cancer immunotherapy.

P3, N=129, Completed, Incyte Corporation | Active, not recruiting --> Completed