IGF2R

Insulin-like growth factor 2 receptor

Score: 0.504 Price: $0.50 Low Druggability Status: active Wiki: IGF2R

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

122

DEBATES

3D Protein Structure

🧬 IGF2R — PDB 2V5O Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.39

Clinical Stage

Approved

Target Class

Receptor

Safety

0.40

Druggability Analysis

Drug Development0.80

Structural Tractability0.85

Target Class0.70

Safety Profile0.40

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

Therapeutic Areas:

Alzheimer's disease Neurodegeneration Cognitive decline Autophagy-related disorders Lysosomal storage diseases Cancer (IGF2-driven tumors)

Druggability Rationale: Despite the availability of structural data and known ligands, IGF2R presents low druggability for neurodegeneration due to its complex mannose-6-phosphate receptor functionality and limited selective targeting strategies. While compounds like linsitinib demonstrate potential IGF pathway modulation, the receptor's primary role in protein trafficking and lack of direct neurogenic signaling mechanisms significantly constrains its therapeutic potential for neurodegenerative interventions. The target's structural complexity and multifunctional nature suggest that precise pharmacological manipulation would require sophisticated molecular engineering approaches beyond current drug discovery capabilities.

Mechanism: Drugs targeting IGF2R typically work by blocking IGF2 binding and signaling through the IGF1R/IGF2R axis, thereby inhibiting mitogenic and anti-apoptotic effects in cancer cells. Alternatively, agents may enhance IGF2 clearance through IGF2R-mediated endocytosis to reduce circulating IGF2 levels and downstream signaling.

Drug Pipeline (4 compounds)

Known Drugs:

Linsitinib (OSI-906) (phase2) — IGF1R/IGF2R pathway inhibition in various cancers

Figitumumab (CP-751,871) (phase2) — IGF1R inhibition with indirect IGF2R pathway modulation in solid tumors

Ganitumab (AMG 479) (phase2) — IGF1R inhibition affecting IGF2-mediated signaling in cancer

MK-0646 (Dalotuzumab) (phase2) — IGF1R/IGF2R axis modulation in advanced cancers

Structural Data:

PDB (20) ✓AlphaFold ✓Cryo-EM ✓

1JPL 1JWG 1LF8 1Q25 1SYO+15 more

UniProt: A0N9R6

Binding Pocket Analysis:

IGF2R contains distinct binding regions: an extracellular ligand-binding domain for IGF2 and mannose-6-phosphate recognition, and a large extracellular ectodomain suitable for monoclonal antibody epitope targeting. Structural data (PDB 1JPL, 1JWG, 1LF8) reveals a horseshoe-shaped mannose-binding pocket and IGF2-interaction interfaces, with cryo-EM and AlphaFold models enabling allosteric modulator design to enhance IGF2 clearance or selectively modulate autophagy signaling.

🧬 3D Protein Structure

🧬 IGF2R — PDB 2V5O Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity challenges include potential cross-reactivity with IGF1R and the mannose-6-phosphate receptor pathway, which may confound therapeutic targeting. Advantage exists in IGF2R's restricted expression pattern and specialized role in lysosomal trafficking, enabling cell-type or tissue-selective modulation through antibody epitope engineering or ligand-selective small molecules.