This tool is for research exploration only. It is not a medical device and does not provide medical advice. Drug candidates, evidence scores, and AI-generated content are not clinical recommendations. Always consult your medical team before making any treatment decisions.

Back to Drug Candidates

Azacitidine

Vidaza

DNA methyltransferase inhibitor (hypomethylating agent)

Evidence Score

58

preclinical
Mechanism of Action

Nucleoside analog that incorporates into DNA and irreversibly traps DNMTs, causing their depletion and progressive DNA demethylation. In SDH-deficient tumors, SDH loss leads to succinate accumulation that competitively inhibits TET1/2/3 (α-KG-dependent DNA demethylases), establishing a genome-wide CpG island methylator phenotype (CIMP). Letouzé et al. (Cancer Cell 2013, PMID: 23707781, DOI: 10.1016/j.ccr.2013.04.018) demonstrated this SDH-driven CIMP mechanism in paraganglioma; Killian et al. (Cancer Discov 2013, PMID: 23550148, DOI: 10.1158/2159-8290.CD-13-0092) identified ~85,000 hypermethylated CpG targets in SDH-deficient GIST vs ~8,400 in KIT-mutant GIST. Azacitidine bypasses the TET inhibition block by directly trapping DNMTs, providing an orthogonal demethylation route independent of TET activity.

Pathway Connections
Epigenetic Dysregulation

Succinate inhibits TET family DNA demethylases and Jumonji-domain histone demethylases, causing global DNA and histone hypermethylation. This silences tumor suppressors and blocks differentiation.

Upstream event:

Succinate inhibits TET1/2/3 and KDM histone demethylases

Downstream effects:

DNA hypermethylation (CIMP phenotype)5-hydroxymethylcytosine lossTumor suppressor silencingHistone hypermethylationDifferentiation block
Molecular Targets

DNMT1

DNA methyltransferase 1

downstream

Maintenance DNA methyltransferase. Contributes to hypermethylation phenotype. Target of azacitidine and decitabine.

UniProt: P26358

DNMT3A

DNA methyltransferase 3A

downstream

De novo DNA methyltransferase. Works with DNMT1 to establish aberrant methylation patterns.

UniProt: Q9Y6K1

Quick Facts

Tumor Type Applicability

All SDH tumors
FDA Approved

Approved Indications

  • Myelodysplastic syndromes
  • Acute myeloid leukemia
ChEMBL IDCHEMBL1489
PubChem CID9444
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.