ACSL4

Long-chain-fatty-acid--CoA ligase 4

Score: 0.335 Price: $0.33 Low Druggability Status: active Wiki: ACSL4

HYPOTHESES

1

PAPERS

14

KG EDGES

357

DEBATES

0

3D Protein Structure

🧬 ACSL4 — PDB 4WB5 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.41

Clinical Stage

Phase III

Target Class

Enzyme

Safety

0.65

Druggability Analysis

Drug Development0.45

Structural Tractability0.70

Target Class0.85

Safety Profile0.65

Key Metrics

PDB Structures:

1

Known Drugs:

4

Approved:

0

In Clinical Trials:

0

Drug Pipeline (4 compounds)

Druggability Rationale: ACSL4 is tractable (0.72 druggability score) as a small-molecule target due to its well-characterized enzymatic active site and validation by existing PPAR-gamma agonists (rosiglitazone, troglitazone) demonstrating in vivo ACSL4 inhibition. The enzyme's role as a metabolic checkpoint in ferroptosis provides a clear mechanistic link to neuroprotection, particularly in neurodegenerative diseases driven by microglial ferroptosis.

Mechanism: Enzyme inhibition — blocking ACSL4 prevents incorporation of PUFAs into membrane phospholipids, reducing ferroptosis susceptibility

Drug Pipeline (4 compounds)

Known Drugs:

Triacsin C (Preclinical)

Rosiglitazone (Approved (diabetes))

Pioglitazone (Approved (diabetes))

PRGL493 (Preclinical)

Structural Data:

PDB (1) ✓AlphaFold ✓Cryo-EM —

UniProt: O60488

🧬 3D Protein Structure

🧬 ACSL4 — PDB 4WB5 Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

ACSL4 selectivity against the five human ACSL isoforms (ACSL1, 3, 5, 6) is achievable but requires optimization, as rosiglitazone's ACSL4 inhibition is an off-target effect of PPAR-gamma binding. Off-target liabilities include unintended PPAR pathway modulation and potential effects on other lipid metabolism enzymes; structure-based design is needed to decouple ACSL4 inhibition from PPAR engagement.

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 (8)

Relevant trials from ClinicalTrials.gov

Active

0

Completed

8

Total Enrollment

700

By Phase

NA: 1 · PHASE1: 1 · PHASE2: 1 · PHASE3: 2 · PHASE4: 2 · Unknown: 1

Glibenclamide (Dose to be Titrated From Starting Dose of 5mg om) Plus Rosiglitazone 4mg om (Increased to 8mg om After 6 Completed

PHASE4 NCT01045590 n=100

Diabetes Mellitus, Type 2

Interventions: titration, titration

Sponsor: GlaxoSmithKline | Started: 2003-12

Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone Completed

PHASE4 NCT02733679 n=27

Ataxia-Telangiectasia

Interventions: Metformin, Pioglitazone

Sponsor: NHS Tayside | Started: 2016-09-29

A Study Of BRL49653C For The Treatment Of Type 2 Diabetes Completed

PHASE3 NCT00523913 n=70

Diabetes Mellitus, Type 2

Interventions: rosiglitazone

Sponsor: GlaxoSmithKline | Started: 2005-11

30-Week Extension to an Initial Combination Study (24 Weeks in Duration) of Sitagliptin With Pioglitazone (0431-064) Completed

PHASE3 NCT01028391 n=317

Type 2 Diabetes Mellitus

Interventions: Sitagliptin 100 mg q.d.+ Pioglitazone 45, Pioglitazone 45 mg q.d. + Sitagliptin 10, Metformin

Sponsor: Merck Sharp & Dohme LLC | Started: 2007-09-01

A Placebo Controlled Safety and Efficacy Study of MSDC-0160 in Type 2 Diabetes With Active Comparator Completed

PHASE2 NCT00760578 n=86

Type 2 Diabetes Mellitus

Interventions: Placebo, Pioglitazone, MSDC-0160 90 mg

Sponsor: Metabolic Solutions Development Company | Started: 2008-09

PPARγ Agonist Treatment for Cocaine Dependence Completed

PHASE1 NCT02774343 n=30

Cocaine Use Disorder, Alcohol Use Disorder

Interventions: Pioglitazone, Placebo, Therapy

Sponsor: The University of Texas Health Science Center, Houston | Started: 2012-08

Effects of Rosiglitazone on Renal Hemodynamics and Proteinuria of Type 2 Diabetic Patients With Renal Insufficiency Due Completed

NA NCT00324675 n=28

Type 2 Diabetes, Overt Diabetic Nephropathy

Interventions: Rosiglitazone, Placebo

Sponsor: Technische Universität Dresden | Started: 2006-08

Effect of Adiponectin Genetic Polymorphism on Rosiglitazone Response Completed

Unknown NCT00501488 n=42

Diabetes Mellitus

Interventions: rosiglitazone

Sponsor: Central South University | Started: 2006-03

Linked Hypotheses (4)

ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia0.847

40 Hz Gamma Entrainment Gates ACSL4-Mediated Ferroptotic Priming to Selectively Eliminate Disease-As0.801

ACSL4-Ferroptotic Priming in Stressed Oligodendrocytes Drives White Matter Degeneration in Alzheimer0.801

ACSL4-Driven Ferroptotic Priming in Disease-Associated Oligodendrocytes Underlies White Matter Degen0.779

Linked Experiments (0)

No linked experiments

Scoring Dimensions

Knowledge Graph (20)

activates (2)

ACSL4→LIPID_PEROXIDATIONACSL4→GPX4

associated with (1)

inhibits (12)

MIR130B3P→ACSL4ACSL4→ALOX12ACSL4→GPX4FASN→ACSL4BAX→ACSL4

▸ Show 7 more

ALOX15→ACSL4GSDMD→ACSL4SCD1→ACSL4HMGCR→ACSL4TNF→ACSL4MLKL→ACSL4ACSL4→MTOR

regulates (2)

MYC→ACSL4ACSL4→MYC

therapeutic target (3)

SLC7A11→ACSL4ACSL4→NRF2ACSL4→SLC7A11

Debate History (0)

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