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Epacadostat
INCB024360
IDO1 inhibitor (indoleamine 2,3-dioxygenase 1 inhibitor)
Evidence Score
22
Selective, orally bioavailable inhibitor of IDO1 (indoleamine 2,3-dioxygenase 1), the rate-limiting enzyme converting tryptophan to kynurenine. In SDH-deficient tumors, the pseudohypoxic HIF-1α program (sustained by succinate-mediated PHD inhibition) drives IDO1 upregulation; aberrant kynurenine pathway activity was confirmed in metastatic SDHB-driven pheochromocytoma/paraganglioma by multi-omics profiling (Zhou et al., Hormones Athens 2026, PMID: 42230482). Kynurenine depletes the essential amino acid tryptophan from the TME, starving T cells, while kynurenine metabolites directly bind aryl hydrocarbon receptor (AhR) in T cells to drive their exhaustion and expand immunosuppressive FoxP3+ regulatory T cells. Epacadostat blocks IDO1 activity, potentially reversing this kynurenine-driven immune suppression in SDH-deficient tumors. Extensive Phase 1/2 clinical data for epacadostat exists in solid tumors (INCB24360-201, NCT02318277). Critical limitation: the Phase 3 ECHO-301 trial of epacadostat + pembrolizumab versus pembrolizumab alone failed in melanoma (Perez et al., J Clin Oncol 2019; DOI: 10.1200/JCO.18.01174), raising serious doubts about IDO1 inhibition as a monotherapy or checkpoint-combination strategy in broadly unselected patients. The SDH-deficient context may be different — IDO1 upregulation here is mechanistically driven by the constitutive pseudohypoxic HIF-1α program rather than interferon-γ induction, and the T-cell suppressive TME is confirmed by orthogonal evidence (PMID 35977513) — but dedicated preclinical validation in SDH-deficient models is absent.
SDH loss creates an immunosuppressive tumor microenvironment through two distinct succinate-dependent mechanisms: (1) extracellular succinate is directly taken up by tumor-infiltrating T cells via MCT1 (SLC16A1), impairing TCA-cycle glucose oxidation in T cells and suppressing IFN-γ secretion and degranulation — demonstrated in human CD4+/CD8+ T cells at tumor-associated succinate concentrations (Gudgeon et al., Cell Rep 2022, PMID 35977513), with RNA-seq of SDH-deficient pheochromocytoma/paraganglioma confirming profound in-vivo IFN-γ signaling suppression; and (2) the pseudohypoxic HIF-1α program drives upregulation of IDO1 (indoleamine 2,3-dioxygenase 1), the rate-limiting enzyme in the tryptophan→kynurenine degradation pathway, with aberrant kynurenine pathway activity confirmed in metastatic SDHB-driven PPGL by multi-omics (PMID 42230482). Together these mechanisms create a profoundly T-cell-hostile TME in SDH-deficient tumors.
Upstream event:
SDH loss → intracellular and extracellular succinate accumulation; HIF-1α stabilization (pseudohypoxia)
Downstream effects:
IDO1
Indoleamine 2,3-dioxygenase 1
Rate-limiting enzyme in tryptophan catabolism via the kynurenine pathway. IDO1 degrades tryptophan to N-formylkynurenine → kynurenine, depleting this essential amino acid from the TME and producing immunosuppressive kynurenine metabolites that exhaust effector T cells and expand FoxP3+ regulatory T cells. In SDH-deficient tumors, the pseudohypoxic HIF-1α program (driven by succinate-mediated PHD inhibition) is known to upregulate IDO1 expression; aberrant kynurenine pathway activity has been confirmed in metastatic SDHB-driven PPGL by multi-omics analysis (PMID 42230482). Target of IDO1 inhibitors including epacadostat.
UniProt: P14902
Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.
Coming in Phase 3
For research exploration only — not medical advice. Consult your doctor before acting on any information.
Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.