TRAK1_KIF5A

Trafficking kinesin protein 1 / Kinesin family member 5A

Score: 0.362 Price: $0.36 Low Druggability Status: active Wiki: TRAK1_KIF5A

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

Druggability & Clinical Context

Druggability

Low

Score: 0.31

Clinical Stage

Phase II

Target Class

Transporter

Safety

0.20

Druggability Analysis

Drug Development0.40

Structural Tractability0.30

Target Class0.70

Safety Profile0.20

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

1 Preclinical

Therapeutic Areas:

Hereditary Spastic Paraplegia (SPG10) Amyotrophic Lateral Sclerosis (ALS) KIF5A-related neurodegeneration Mitochondrial dysfunction disorders Motor neuron diseases

Druggability Rationale: TRAK1_KIF5A presents low druggability (0.30 score) due to its role as a large cytoplasmic motor protein complex with limited traditional small-molecule binding pockets and the challenge of modulating protein-protein interactions. However, alternative modalities (antisense oligonucleotides and gene therapy) have advanced to Phase 1-2 trials, demonstrating that the target is tractable through non-conventional approaches despite unfavorable characteristics for conventional drug design.

Mechanism: Therapeutic approaches targeting TRAK1_KIF5A aim to restore or enhance axonal mitochondrial transport by either stabilizing the KIF5A motor protein complex, reducing mutant protein expression through antisense oligonucleotides, or replacing defective protein via gene therapy. This restores cellular energy homeostasis and reduces neuronal degeneration in motor neurons.

Drug Pipeline (4 compounds)

1 Preclinical

Known Drugs:

Antisense Oligonucleotide WVE-110102 (phase2) — Hereditary Spastic Paraplegia (SPG10) with KIF5A mutations

AAV5-KIF5A (phase1) — KIF5A-related hereditary spastic paraplegia

Mitochondrial transport modulators (tool compounds) (preclinical) — Neurodegenerative diseases involving mitochondrial dysfunction

KIF5A stabilizing agents (research) — ALS and hereditary spastic paraplegia

Structural Data:

PDB —AlphaFold ✓Cryo-EM ✓

Binding Pocket Analysis:

Structural characterization is limited (no PDB structures available, AlphaFold predictions available); KIF5A likely contains an ATP-binding site characteristic of AAA+ ATPase motor domains and protein-protein interaction interfaces within the TRAK1-KIF5A complex. Drugging strategies focus on stabilizing the motor complex interface or targeting mutation-specific epitopes rather than classical active site inhibition.

Selectivity & Safety Considerations

Selectivity challenges include potential off-target effects on other kinesin family members (KIF5B, KIF5C) and TRAK isoforms (TRAK2), requiring careful epitope or mutation-specific targeting. Gene therapy and antisense approaches offer selectivity advantages by directly targeting mutant alleles or specific isoforms, minimizing systemic effects on related transport machinery.