Druggability & Clinical Context
Druggability
Low
Score: 0.45
Druggability Analysis
Structural Tractability0.95
Key Metrics
PDB Structures:
85
Known Drugs:
2
Approved:
0
In Clinical Trials:
0
Drug Pipeline (2 compounds)
Therapeutic Areas:neurodegenerative diseases (Alzheimer's, Parkinson's) age-related cognitive decline neuroprotection DNA repair disorders cancer (NAD+-dependent vulnerabilities) metabolic disorders aging-related conditions
Druggability Rationale: NAMPT is highly druggable (0.80 score) due to its well-defined active site, abundant structural data (85 PDB structures at 1.32 Å resolution), and established precedent with clinical candidates FK866 and CHS-828. However, clinical translation has been challenged by toxicity and selectivity issues rather than target validation, suggesting the enzyme itself is tractable but requires optimization of inhibitor properties.
Mechanism: Small molecule competitive inhibitors of NAD+ biosynthesis enzyme
Drug Pipeline (2 compounds)
Known Drugs:FK866 (failed_phase_2) — cancer
CHS-828 (failed_phase_2) — cancer
Structural Data:PDB (85) ✓AlphaFold ✓Cryo-EM —
Binding Pocket Analysis:The active site accommodates nicotinamide and the PRPP substrate in a well-characterized pocket (exemplified by PDB 2GVG, 2H3B), with both ATP-competitive and allosteric binding modes described. The 1.32 Å resolution structures reveal precise catalytic geometry suitable for structure-based drug design of next-generation competitive inhibitors with improved selectivity profiles.
Selectivity & Safety Considerations
NAMPT selectivity is favorable as the enzyme has limited isoforms (primarily intracellular form), but off-target liabilities to other NAD+-consuming enzymes (PARPs, sirtuins) and broad NAD+ depletion effects present selectivity challenges. Tissue-specific NAD+ dependence may cause collateral damage in energy-demanding tissues (neurons, muscle), limiting therapeutic windows.
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