IDH2

Isocitrate Dehydrogenase 2

Score: 0.691 Price: $0.69 High Druggability Status: active Wiki: IDH2

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

166

DEBATES

3D Protein Structure

🧬 IDH2 — PDB 5I95 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

High

Score: 0.90

Clinical Stage

Approved

Target Class

Enzyme

Safety

0.60

Druggability Analysis

Drug Development0.60

Structural Tractability0.85

Target Class0.85

Safety Profile0.60

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (2 compounds)

Therapeutic Areas:

Acute myeloid leukemia (AML) Neurodegenerative diseases (Parkinson's, Alzheimer's) Mitochondrial dysfunction disorders Oxidative stress-related neuroinflammation Gliomas and brain tumors Metabolic neuroprotection

Druggability Rationale: IDH2 is highly druggable (score: 0.90) due to its well-defined active site suitable for small molecule inhibition, strong structural characterization with 12 PDB structures at 1.54 Å resolution, and clinical validation via two FDA-approved drugs (Enasidenib, Ivosidenib) targeting mutant IDH2 in AML. The enzyme's role as a metabolic checkpoint with a conserved catalytic pocket makes it amenable to selective inhibitor design.

Mechanism: Small molecule inhibitor of mutant IDH2 enzyme activity

Drug Pipeline (2 compounds)

Known Drugs:

Enasidenib (Approved) — Acute myeloid leukemia

Ivosidenib (Approved) — Acute myeloid leukemia

Structural Data:

PDB (12) ✓AlphaFold ✓Cryo-EM —

3BLV 3BLW 3BLX 4JA8 5H3E+7 more

UniProt: A0A1P8A7C0

Binding Pocket Analysis:

IDH2 features a conserved isocitrate/substrate binding pocket at the active site with a characteristic metal coordination site (typically Mg2+) that stabilizes substrate binding; small molecule inhibitors exploit mutations in this pocket (R140Q, R172K) that are prevalent in hematologic malignancies, achieving selectivity through mutation-specific binding geometries revealed across the 12 available crystal structures.

🧬 3D Protein Structure

🧬 IDH2 — PDB 5I95 Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

Selectivity between IDH2 and the cytosolic isoform IDH1 is critical to avoid off-target metabolic disruption; existing approved drugs achieve this through mitochondrial-targeting and mutant-selective binding modes. Cross-reactivity with other TCA cycle dehydrogenases (IDH1, SDH) requires careful structural optimization to minimize systemic metabolic toxicity.