CHMP2B

Charged multivesicular body protein 2B

Score: 0.508 Price: $0.51 Low Druggability Status: active Wiki: CHMP2B

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

172

DEBATES

3D Protein Structure

🧬 CHMP2B — PDB 6HRB Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.32

Clinical Stage

Phase II

Target Class

Other

Safety

0.30

Druggability Analysis

Drug Development0.45

Structural Tractability0.70

Target Class0.50

Safety Profile0.30

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

1 Preclinical

Therapeutic Areas:

Frontotemporal Dementia (FTD) Amyotrophic Lateral Sclerosis (ALS) C9ORF72-related neurodegeneration Progranulin (GRN) mutation-associated FTD Protein aggregation disorders Neuroinflammation

Druggability Rationale: CHMP2B has low druggability (0.30) as a structural ESCRT-III component lacking a well-defined ligand-binding pocket, making direct small-molecule inhibition unfeasible. Current therapeutic strategies circumvent this limitation by targeting upstream regulators (autophagy enhancers, GLP-1 agonists) or modulating CHMP2B expression indirectly via antisense oligonucleotides rather than occupying a conserved binding site.

Mechanism: Therapeutic agents targeting CHMP2B would modulate ESCRT-III complex function to enhance endosomal sorting and autophagy, potentially clearing protein aggregates associated with frontotemporal dementia or compensating for loss-of-function mutations. Strategies include antisense oligonucleotides to modulate protein expression, autophagy enhancers to promote cellular clearance pathways, or small molecules that stabilize ESCRT-III complex assembly and function.

Drug Pipeline (4 compounds)

1 Preclinical

Known Drugs:

ISIS 420915 (Antisense against Tau) (phase2) — Frontotemporal Dementia associated with Progranulin mutations

BIIB078 (phase1) — C9ORF72-related frontotemporal dementia and ALS

GLP-1 Receptor Agonists (Liraglutide derivatives) (phase2) — Neuroinflammation in Frontotemporal Dementia

Autophagy modulators (Experimental compounds) (preclinical) — ESCRT-III pathway dysfunction and neurodegeneration

Structural Data:

PDB (1) ✓AlphaFold ✓Cryo-EM —

2JQK

UniProt: Q9UQN3

Binding Pocket Analysis:

PDB 2JQK reveals CHMP2B as a largely α-helical structural protein without a canonical small-molecule binding pocket; targeting focuses on protein-protein interaction interfaces within the ESCRT-III complex or allosteric modulation of assembly conformations rather than orthosteric sites. Therapeutic engagement likely requires stabilization of functional complex architecture or modulation of oligomerization state.

🧬 3D Protein Structure

🧬 CHMP2B — PDB 6HRB Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

CHMP2B selectivity challenges stem from high homology with other ESCRT-III family members (CHMP2A, CHMP3, CHMP4); antisense and autophagy modulator approaches offer better selectivity through sequence-specific targeting. Off-target effects on general autophagy or endosomal sorting pathways represent the primary risk for systemic modulators.