Druggability & Clinical Context
Druggability
Low
Score: 0.31
Druggability Analysis
Structural Tractability0.30
Key Metrics
PDB Structures:
0
Known Drugs:
4
Approved:
0
In Clinical Trials:
2
Drug Pipeline (4 compounds)
1 Preclinical
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 ✓
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.
Clinical Trials (8)
Relevant trials from ClinicalTrials.gov
By Phase
NA: 5 · PHASE1: 1 · PHASE2: 1 · Unknown: 1
NA
NCT00486551
n=26
Tourette Syndrome, Chronic Tic Disorder, Oppositional Defiant Disorder
Interventions: Anger control training
Sponsor: Yale University | Started: 2001-08
NA
NCT06909045
n=130
Deep Brain Stimulation, Parkinson Disease
Interventions: Adaptive DBS, Continue DBS
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC | Started: 2026-01-27
PHASE1
NCT00843739
n=90
Parkinson's Disease
Interventions: EMST - Active Treatment, sham EMST
Sponsor: University of Florida | Started: 2004-01
Unknown
NCT03292575
n=441
Stroke
Interventions: Anticoagulants
Sponsor: Centre Hospitalier Universitaire Dijon | Started: 2016-01
NA
NCT01924312
n=80
Cerebrovascular Disease, Mild Cognitive Impairment
Interventions: Heart Health Intervention
Sponsor: Gregory Jicha, 323-5550 | Started: 2013-05
NA
NCT06306365
n=35
Executive Functions
Interventions: Modern board game-based learning
Sponsor: European University Miguel de Cervantes | Started: 2024-02-07
NA
NCT02260167
n=25
Alzheimer's Disease, Dementia
Interventions: A mix of natural treatments and medicati
Sponsor: Practitioners Alliance Network | Started: 2014-09
PHASE2
NCT03987295
n=33
Frontotemporal Dementia
Interventions: AL001
Sponsor: Alector Inc. | Started: 2019-09-27