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Dichloroacetate (DCA)

Pyruvate dehydrogenase kinase inhibitor

Evidence Score

35

preclinical
Mechanism of Action

Inhibits PDK1-4, reactivating pyruvate dehydrogenase and forcing pyruvate into the TCA cycle. In SDH-deficient cells, this pushes metabolites into a broken TCA cycle, potentially increasing ROS and triggering apoptosis.

Pathway Connections
Pseudohypoxia / HIF Pathway

Succinate accumulation inhibits PHD enzymes, stabilizing HIF-1α and HIF-2α regardless of oxygen levels. This drives angiogenesis (VEGF), metabolic reprogramming (glycolysis shift), and growth factor signaling.

Upstream event:

Succinate inhibits PHD1/2/3 (α-KG-dependent dioxygenases)

Downstream effects:

HIF-1α/2α stabilizationVEGF upregulationGLUT1/3 upregulationGlycolytic enzyme inductionEPO production
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

PDK1

Pyruvate dehydrogenase kinase 1

downstream

HIF target that suppresses pyruvate entry into TCA cycle, reinforcing glycolytic shift. Target of dichloroacetate (DCA).

UniProt: Q15118

Quick Facts
Not FDA Approved
ChEMBL IDCHEMBL1213352
PubChem CID54675
Evidence

Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.

Coming in Phase 3

AI Analysis

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