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Metformin

Glucophage

Biguanide / AMPK activator

Evidence Score

40

preclinical
Mechanism of Action

Inhibits mitochondrial Complex I and activates AMPK, thereby inhibiting mTOR signaling. The primary rationale in SDH-deficient tumors is AMPK-mediated mTOR suppression, not Complex I inhibition: Sokolov et al. (PMID 42239110, 2026) demonstrated that SDH-deficient cells adaptively suppress Complex I activity, meaning metformin's Complex I target is already downregulated. The AMPK→mTOR axis remains plausible but is off-mechanism relative to the original Complex I rationale.

Pathway Connections
mTOR / PI3K / AKT

Metabolic reprogramming from SDH loss activates the PI3K/AKT/mTOR signaling axis, promoting cell growth, proliferation, and survival. Multiple upstream inputs converge on mTOR.

Upstream event:

HIF-mediated growth factor signaling + metabolic stress + AMPK dysregulation

Downstream effects:

Cell growth and proliferationProtein synthesisMetabolic reprogrammingSurvival signaling
Oxidative Stress / ROS

Complex II dysfunction causes electron leak in the electron transport chain, increasing reactive oxygen species (ROS). This drives DNA damage but also creates a therapeutic vulnerability.

Upstream event:

Impaired electron flow through Complex II → electron leak

Downstream effects:

Increased ROS productionOxidative DNA damageGenomic instabilityPARP activation for DNA repairTherapeutic vulnerability to further ROS stress
Molecular Targets

MTOR

Mechanistic target of rapamycin

downstream

Central growth/metabolism regulator activated downstream of SDH loss. Target of everolimus and temsirolimus.

UniProt: P42345

Quick Facts

Tumor Type Applicability

All SDH tumors
FDA Approved

Approved Indications

  • Type 2 diabetes mellitus
ChEMBL IDCHEMBL1431
PubChem CID4091
Evidence

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.

AI Analysis

Have Claude analyze this drug's repurposing potential for SDH-deficient diseases.