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.

These findings suggest a potential inhibitory mechanism for PF-06840003 and offer valuable structural insights for the rational design of potent IDO1 inhibitors. It should be noted that the inhibitory activity of the designed lead compounds is based solely on computational predictions; experimental validation through in vitro and in vivo studies is still required to confirm their actual inhibitory effects and pharmacokinetic properties.

P2, N=24, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Sep 2025 --> Sep 2026

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.

Cohort A received RT + nivolumab with escalating BMS-986205 doses in MGMT unmethylated GBM patients. Cohort B received the highest dose of BMS-986205 with nivolumab and standard RT/temozolomide (TMZ)

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

The results indicated that compounds I-1 and I-2 exhibited activity similar to that of Epacadostat in inhibiting recombinant hIDO1 and hIDO1 expression in HeLa cells...The physicochemical properties along with pharmacokinetic profiles of both compounds were also predicted, and they were found to possess favorable characteristics. The active compounds developed in this research may serve as valuable references for discovering highly effective IDO1 inhibitors.