FLOT1

Flotillin 1

Score: 0.448 Price: $0.45 Low Druggability Status: active Wiki: FLOT1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 FLOT1 — PDB 1WIN Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.35

Clinical Stage

Phase II

Target Class

Structural Protein

Safety

0.40

Druggability Analysis

Drug Development0.35

Structural Tractability0.85

Target Class0.50

Safety Profile0.40

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

1 Preclinical

Therapeutic Areas:

Alzheimer's disease Neuroinflammation Amyloid-beta pathology Tau-related neurodegeneration Protein misfolding diseases Frontotemporal dementia Parkinson's disease

Druggability Rationale: FLOT1 presents low druggability (0.30) primarily due to its role as a structural scaffold protein lacking a well-defined enzymatic active site, making traditional small-molecule inhibition challenging. While 19 PDB structures and AlphaFold models provide structural insight, the protein's dependence on lipid interactions and membrane organization rather than ligand binding limits conventional drug development approaches; however, antisense oligonucleotide strategies show promise for indirect modulation.

Mechanism: Drug candidates would modulate FLOT1-mediated lipid raft organization and signaling platform assembly, thereby disrupting pathological protein trafficking and reducing amyloid-beta or tau-related pathology in neurodegenerative diseases. FLOT1 inhibitors would interfere with membrane scaffold formation necessary for aberrant signaling in neuroinflammatory and proteinopathic cascades.

Drug Pipeline (4 compounds)

1 Preclinical

Known Drugs:

Methyl-beta-cyclodextrin (research) — Lipid raft disruption (tool compound); potential neuroprotection

Filipin III (preclinical) — Cholesterol-dependent lipid raft organization; research tool

Dynasore (research) — Endocytic pathway modulation affecting flotillin trafficking

FLT1-targeting antisense oligonucleotide (investigational) (phase1) — Amyloid-beta accumulation and neurodegeneration (preclinical evidence)

Structural Data:

PDB (19) ✓AlphaFold ✓Cryo-EM ✓

7TX6 7TX7 7XPZ 7XQ0 7XQ1+14 more

UniProt: A0A0G2JJQ6

Binding Pocket Analysis:

FLOT1 lacks a conventional active site but features a lipid-binding interface and a DHPH domain (residues ~1-80) that mediates protein-protein interactions within membrane scaffolds; the best-resolution structure (3.5 Å) reveals a banana-shaped oligomerization interface suitable for allosteric modulation or stabilization by small molecules rather than occupancy-based inhibition.

🧬 3D Protein Structure

🧬 FLOT1 — PDB 1WIN Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

FLOT1 selectivity must account for its functional overlap with FLOT2, the paralogous isoform with similar lipid raft organization roles, requiring isoform-selective inhibition strategies to avoid compensatory mechanisms. Off-target disruption of general membrane organization and endocytic trafficking poses risk, necessitating cell-type or tissue-specific delivery approaches to minimize systemic toxicity.