CHMP4B

Charged multivesicular body protein 4B

Score: 0.442 Price: $0.44 Low Druggability Status: active Wiki: CHMP4B

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 CHMP4B — PDB 4ABM Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.30

Clinical Stage

Phase II

Target Class

Other

Safety

0.30

Druggability Analysis

Drug Development0.35

Structural Tractability0.70

Target Class0.50

Safety Profile0.30

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

2 Preclinical

Therapeutic Areas:

Neurodegenerative diseases (autophagy dysfunction-linked neurodegeneration) Frontotemporal dementia (FTD-related CHMP mutations) Cancer (ESCRT-dependent survival and exosome biogenesis) Viral infections (HIV, dengue - ESCRT-dependent budding) Lysosomal storage disorders Membrane trafficking disorders

Druggability Rationale: CHMP4B presents low druggability (0.30 score) due to its role as a structural ESCRT-III component lacking defined ligand-binding pockets; while 2 crystal structures (PDB: 3C3Q, 3UM3) at 1.7Å resolution exist, the target primarily functions through transient protein-protein interactions rather than orthosteric binding sites, making traditional small-molecule inhibition challenging despite preclinical ESCRT modulators (ML-SI3, Spautin-1) showing pathway-level effects.

Mechanism: CHMP4B-targeting drugs would inhibit or modulate ESCRT-III complex assembly and membrane scission, disrupting cellular degradation pathways (autophagy, lysosomal trafficking) and potentially inhibiting viral budding or cancer cell survival. Therapeutics could involve blocking protein-protein interactions within the ESCRT complex or stabilizing/destabilizing CHMP4B conformational states.

Drug Pipeline (4 compounds)

2 Preclinical

Known Drugs:

ML-SI3 (ESCRT modulator) (preclinical) — Cancer and viral infection (ESCRT-dependent processes)

Spautin-1 (research) — Autophagy modulation through ESCRT disruption

VPS34 inhibitors (SAR405, VPS34-IN1) (phase1) — Advanced malignancies via ESCRT-autophagy pathway

ALIX antagonists (investigational) (preclinical) — Viral infections and membrane trafficking disorders

Structural Data:

PDB (2) ✓AlphaFold ✓Cryo-EM —

3C3Q 3UM3

UniProt: Q9H444

Binding Pocket Analysis:

CHMP4B lacks classical small-molecule binding pockets; structural data suggest potential allosteric modulation sites at protein-protein interaction interfaces (CHMP3/CHMP2B binding regions) or cryptic pockets addressable through conformational stabilization strategies; most promising approach involves targeting transient oligomerization states or membrane-binding surfaces rather than deep orthosteric cavities.

🧬 3D Protein Structure

🧬 CHMP4B — PDB 4ABM Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity remains a major challenge as CHMP4B is one of six ESCRT-III paralogs with overlapping functions; inhibition of CHMP4B may be compensated by CHMP2B, CHMP3, or CHMP6 activity, limiting therapeutic specificity and potentially causing off-target effects on essential cellular degradation pathways; isoform-selective modulation would require targeting unique conformational states or interaction surfaces rather than conserved catalytic sites.