FOXO3

Forkhead box protein O3

Score: 0.584 Price: $0.58 Low Druggability Status: active Wiki: FOXO3

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

590

DEBATES

3D Protein Structure

🧬 FOXO3 — PDB 2UZK Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.42

Clinical Stage

Approved

Target Class

Transcription Factor

Safety

0.35

Druggability Analysis

Drug Development0.75

Structural Tractability0.70

Target Class0.50

Safety Profile0.35

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

1 Approved · 2 Preclinical

Therapeutic Areas:

Neurodegenerative diseases (Alzheimer's, Parkinson's disease) Neuroinflammation and neuroprotection Cancer (autophagy-mediated cell death) Metabolic disorders and type 2 diabetes Aging-related cognitive decline Stroke and ischemic neuronal injury

Druggability Rationale: FOXO3 presents medium druggability (0.55) due to its transcription factor nature, which traditionally poses challenges for direct small-molecule binding; however, the availability of high-resolution crystal structures (PDB 2K86 at 1.35 Å resolution) and successful indirect modulation via the PI3K/Akt pathway demonstrate viable drugging strategies. Existing approved drugs (thiazolidinediones) and multiple preclinical candidates validate the target's tractability despite its classification as a challenging protein class.

Mechanism: FOXO3-targeting drugs modulate the PI3K/Akt/FOXO3 signaling pathway to promote FOXO3 nuclear translocation and transcriptional activity, enhancing autophagy, stress resistance, and apoptosis in cancer cells. Indirect activators increase FOXO3 expression or prevent its degradation, thereby amplifying cellular protective responses.

Drug Pipeline (4 compounds)

1 Approved · 2 Preclinical

Known Drugs:

AS1842856 (preclinical) — Cancer, metabolic disorders

Thiazolidinediones (e.g., Pioglitazone) (approved) — Type 2 diabetes mellitus

Resveratrol (research) — Aging, neurodegeneration, cancer prevention

A-769662 (preclinical) — Metabolic disorders, cancer

Structural Data:

PDB (1) ✓AlphaFold ✓Cryo-EM —

2K86

UniProt: O43524

Binding Pocket Analysis:

FOXO3 contains a highly conserved forkhead DNA-binding domain (DBD) characterized by a winged helix-turn-helix structure; allosteric pockets outside the DBD represent more selective binding opportunities for small molecules targeting post-translational modifications or protein-protein interactions. The 1.35 Å resolution structure enables rational design of ligands targeting the nuclear localization signal (NLS) regulation or protein degradation pathway modulators rather than direct transcriptional inhibition.

🧬 3D Protein Structure

🧬 FOXO3 — PDB 2UZK Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

FOXO family selectivity is a key challenge, as FOXO1, FOXO4, and FOXO6 share highly conserved DNA-binding domains and overlapping regulatory roles; off-target engagement with other forkhead transcription factors must be carefully evaluated. Pathway-based indirect approaches (PI3K/Akt inhibition) offer inherent selectivity advantages but risk pleiotropy across multiple FOXO isoforms.