TARDBP

TAR DNA-binding protein 43

Score: 0.514 Price: $0.51 Low Druggability Status: active Wiki: TARDBP

🟡 ALS / Motor Neuron Disease 🧠 Neurodegeneration

HYPOTHESES

6

PAPERS

57

KG EDGES

575

DEBATES

1

3D Protein Structure

🧬 TARDBP — PDB 2N3X Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.43

Clinical Stage

Phase III

Target Class

Transcription Factor

Safety

0.20

Druggability Analysis

Drug Development0.45

Structural Tractability0.85

Target Class0.50

Safety Profile0.20

Key Metrics

PDB Structures:

29

Known Drugs:

1

Approved:

0

In Clinical Trials:

0

Drug Pipeline (1 compounds)

1 Preclinical

Druggability Rationale: TARDBP presents significant druggability challenges due to its classification as a transcription factor with intrinsic RNA-binding function, which typically lack well-defined small molecule binding pockets suitable for conventional drug design. However, the target remains tractable given 29 available PDB structures with 0.75 Å resolution, cryo-EM data, and successful proof-of-concept with Tofersen (antisense oligonucleotide), suggesting that indirect modulation or allosteric approaches may overcome the low 0.30 druggability score better than orthosteric inhibition.

Mechanism: RNA-binding and transcription regulation, challenging for small molecule targeting

Drug Pipeline (1 compounds)

1 Preclinical

Known Drugs:

Tofersen (investigational) — ALS

Structural Data:

PDB (29) ✓AlphaFold ✓Cryo-EM ✓

2CQG 2N2C 2N3X 2N4G 2N4H+24 more

UniProt: A0A087WYY0

🧬 3D Protein Structure

🧬 TARDBP — PDB 2N3X Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity challenges are moderate since TDP-43 is predominantly expressed in neurons and muscle, reducing potential off-target toxicity in other tissues; however, the RNA-binding domain is shared across multiple RBP families, requiring careful structural selectivity to avoid inhibiting related proteins like FUS or hnRNPs that may compensate for TDP-43 loss.

3D Protein Structure

PDB: Open in RCSB AlphaFold model

Interactive 3D viewer powered by RCSB PDB / Mol*. Use mouse to rotate, scroll to zoom.

Clinical Trials (7)

Relevant trials from ClinicalTrials.gov

Active

2

Completed

3

Total Enrollment

616

By Phase

PHASE1: 1 · PHASE3: 3 · Unknown: 3

A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Participants With Superoxide Dismutase 1 (SOD- Not Yet Recruiting

Unknown NCT07259980 n=125

Amyotrophic Lateral Sclerosis

Interventions: Tofersen

Sponsor: Biogen | Started: 2026-03-31

A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Muta Active Not Recruiting

PHASE3 NCT04856982 n=158

Amyotrophic Lateral Sclerosis Associated

Interventions: Tofersen, Placebo

Sponsor: Biogen | Started: 2021-05-17

Long-Term Evaluation of BIIB067 (Tofersen) Completed

PHASE3 NCT03070119 n=139

ALS Caused by Superoxide Dismutase 1 (SO

Interventions: Tofersen

Sponsor: Biogen | Started: 2017-03-08

An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inhe Completed

PHASE3 NCT02623699 n=176

Amyotrophic Lateral Sclerosis

Interventions: Tofersen, Placebo

Sponsor: Biogen | Started: 2016-01-20

A Study to Evaluate Safety, Tolerability, and Distribution of a Microdose of Radiolabeled BIIB067 (99mTc-MAG3-BIIB067) C Completed

PHASE1 NCT03764488 n=8

Healthy Volunteers

Interventions: Tofersen, 99mTc-MAG3-BIIB067

Sponsor: Biogen | Started: 2018-12-20

Expanded Access Program for Tofersen in Participants With Superoxide Dismutase 1-Amyotropic Lateral Sclerosis Approved For Marketing

Unknown NCT04972487

Superoxide Dismutase 1-Amyotropic Latera

Interventions: Tofersen

Sponsor: Biogen

Rehabilitation in SOD1 ALS Treated With Tofersen Unknown

Unknown NCT05725759 n=10

Amyotrophic Lateral Sclerosis, Lou Gehrig Disease, Familial Amyotrophic Lateral Sclerosis

Interventions: Rehabilitation

Sponsor: Washington University School of Medicine | Started: 2022-11-08

Linked Hypotheses (8)

Cross-Seeding Prevention Strategy0.689

Glial Neuroinflammatory Amplification by TDP-43 Pathology0.680

Glycine-Rich Domain Competitive Inhibition0.640

Synaptic RNA Metabolism Dysregulation0.620

Cytosolic TDP-43 aggregation sequesters SNAP29 and syntaxin-17, blocking autophagosome-lysosome fusi0.600

Cryptic Exon Silencing Restoration0.531

G3BP1-TDP-43 Cross-Seeding Drives Co-Aggregation That Prion-Spreads Across Neural Circuits0.490

RNA-Binding Competition Therapy for TDP-43 Cross-Seeding0.465

Linked Experiments (7)

TDP-43 mitochondrial invasion and DNA release via mPTP0.900

TDP-43 mutant mouse model cGAS/STING pathway analysis0.900

TDP-43 mitochondrial invasion and mtDNA release in iPSC motor neurons0.900

cGAS/STING pathway validation in TDP-43 mutant mice0.850

cGAMP biomarker analysis in ALS patient spinal cord samples0.800

TDP-43 pathology prevalence and distribution in AD cases0.800

Cognitive impact of TDP-43 pathology in AD patients0.700

Scoring Dimensions

Knowledge Graph (20)

associated with (6)

TARDBP→neurodegenerationSTIP1→TARDBPLGALS3→TARDBPHSPA8→TARDBPMCOLN1→TARDBP

▸ Show 1 more

SQSTM1→TARDBP

co discussed (10)

TGM2→TARDBPTARDBP→PRMT1TARDBP→PARP1TARDBP→HSPA1ATARDBP→G3BP1

▸ Show 5 more

TARDBP→SRPK1SETX→TARDBPTARDBP→HNRNPA2B1TARDBP→NPM1TARDBP→SYNCRIP

expressed in (1)

interacts with (3)

TARDBP→NTN1TARDBP→SNRNP70TARDBP→NTN3

Debate History (1)

Should TARDBP (TAR DNA-binding protein 43) be prioritized as a therapeutic targe2026-04-22