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

Tazemetostat

Tazverik

EZH2 inhibitor (PRC2 inhibitor)

Evidence Score

65

clinical trial
Mechanism of Action

Selective, orally bioavailable inhibitor of EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which writes the repressive H3K27me3 histone mark. In SDH-deficient tumors, succinate accumulation inhibits KDM6A (UTX) and KDM6B (JMJD3) — the α-KG-dependent demethylases that erase H3K27me3 — causing global H3K27me3 accumulation and silencing of tumor suppressor and differentiation genes (Letouzé et al., Cancer Cell 2013, PMID: 23862161; Killian et al., Cancer Discov 2013, PMID: 23575604). Tazemetostat blocks EZH2's catalytic activity, reducing further H3K27me3 deposition. FDA-approved for SMARCB1-null epithelioid sarcoma, which shares the mechanism of PRC2 dependency via a different upstream loss. Phase 2 trials in sarcoma and solid tumors ongoing (NCT03213665). Direct evidence in SDH-deficient paraganglioma cell lines: Loriot et al. demonstrated H3K27me3 as an epigenetic vulnerability in paraganglioma (PMID: 25633189).

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

EZH2

Enhancer of zeste homolog 2 (PRC2 catalytic subunit)

synthetic_lethal

Histone H3K27 methyltransferase and catalytic subunit of PRC2. Succinate inhibits KDM6A (UTX) and KDM6B (JMJD3), the H3K27me3-erasing demethylases, causing H3K27me3 accumulation in SDH-deficient tumors. EZH2 inhibition prevents further H3K27me3 deposition, potentially reactivating silenced differentiation and tumor suppressor programs. Target of tazemetostat.

UniProt: Q15910

Quick Facts
FDA Approved

Approved Indications

  • Epithelioid sarcoma (SMARCB1-null, locally advanced or metastatic)
  • Relapsed/refractory follicular lymphoma (EZH2-mutant or wild-type)
ChEMBL IDCHEMBL4297497
PubChem CID46843906
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.