linrodostat (BMS-986205)

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.

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

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)

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.

Prior to these findings, clinical management centered around surgical excision. The use of molecular compounds such as indoximob, epacadostat, BMS-986205 and navoximod, that directly target IDO1 opens new possibilities for targeting these tumors, improving clinical outcomes, and minimizing the morbidities often associated with surgery.

P1, N=18, Active, not recruiting, Northwestern University | Trial primary completion date: Feb 2025 --> Feb 2027

Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells...The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

P3, N=855, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Apr 2025 --> Nov 2025

Actualization of a patient-specific I-O combination treatment selection strategy is feasible, however, determination of de novo integral biomarker thresholds of novel I-O targets to facilitate effective treatment of PD-1-refractory cancer remains fraught. These data emphasize the difficulty of integral biomarker development for I-O in translating from immunotherapy treatment-naïve biospecimens to the selection of patients in the PD-1-refractory state.

P1/2, N=229, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed | Trial completion date: Nov 2026 --> Feb 2025 | Trial primary completion date: Nov 2026 --> Feb 2025

A recent phase I/II study tested the IDO1 inhibitor linrodostat with nivolumab +/- ipilimumab in patients with advanced solid tumors. While efficacy was not augmented, correlative analyses identified TDO2 as a resistance mechanism; dual targeting may be necessary to realize improved response to PD-1 inhibition.

P2, N=45, Active, not recruiting, Thomas Jefferson University | Terminated --> Active, not recruiting | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Jun 2024 --> Dec 2025