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AZD3965
MCT1 inhibitor (monocarboxylate transporter 1 inhibitor, SLC16A1)
Evidence Score
30
Potent, selective, orally bioavailable inhibitor of monocarboxylate transporter 1 (MCT1/SLC16A1). The primary rationale in SDH-deficient tumors is immune restoration: Gudgeon et al. (Cell Rep 2022, PMID: 35977513) demonstrated that SDH-deficient pheochromocytoma and paraganglioma tumors release succinate into the tumor microenvironment at concentrations that are directly taken up by CD4+ and CD8+ T cells via MCT1. This succinate uptake inhibits succinyl-CoA synthetase and impairs T-cell TCA-cycle glucose oxidation, suppressing degranulation and IFN-γ secretion — confirmed by RNA-sequencing showing profound in-vivo suppression of IFN-γ-induced genes in SDH-deficient versus SDH-intact tumors. MCT1 inhibition with AZD3965 would block this immunosuppressive succinate transport into T cells, potentially restoring anti-tumor effector function. AZD3965 also disrupts metabolic symbiosis between glycolytic and oxidative tumor cell populations (blocking lactate recycling), a secondary anti-tumor mechanism. Phase 1 data in lymphoma and solid tumors (NCT01791595): MTD established; dose-limiting retinal toxicity observed at higher doses (VEGFA-independent, manageable with ophthalmological monitoring). No SDH-deficient-specific trial data yet. Key limitation: AZD3965 would block MCT1 in all cell types, including potentially activated T cells that use lactate import during expansion — the net immunological balance in the SDH-specific succinate-rich context remains to be tested empirically.
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:
SLC16A1
Monocarboxylate transporter 1 (MCT1)
Bidirectional plasma-membrane transporter for small monocarboxylates including lactate, pyruvate, and succinate. In the SDH-deficient tumor microenvironment, high extracellular succinate is transported into tumor-infiltrating CD4+ and CD8+ T cells via MCT1, inhibiting succinyl-CoA synthetase and impairing TCA-cycle glucose oxidation; the net effect is suppressed IFN-γ secretion and degranulation — demonstrated in human T cells at physiological tumor-associated succinate concentrations (PMID 35977513). MCT1 inhibition would block this immunosuppressive succinate uptake in T cells while also disrupting metabolic symbiosis between glycolytic and oxidative tumor cells (lactate recycling). Target of AZD3965.
UniProt: P53985
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.