PPARGC1A

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

Score: 0.569 Price: $0.57 Low Druggability Status: active Wiki: PPARGC1A

🧠 Neurodegeneration

HYPOTHESES

3

PAPERS

49

KG EDGES

590

DEBATES

1

3D Protein Structure

🧬 PPARGC1A — PDB 3CS8 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.43

Clinical Stage

Approved

Target Class

Transcription Factor

Safety

0.40

Druggability Analysis

Drug Development0.75

Structural Tractability0.70

Target Class0.50

Safety Profile0.40

Key Metrics

PDB Structures:

7

Known Drugs:

3

Approved:

1

In Clinical Trials:

0

Drug Pipeline (3 compounds)

1 Approved · 2 Preclinical

Druggability Rationale: PPARGC1A has medium druggability (0.55) due to its intrinsic challenge as a transcriptional coactivator lacking a deep orthosteric binding pocket, yet existing approved drugs (Bezafibrate) and investigational compounds (AICAR, ZLN005) demonstrate indirect and direct modulatory approaches are viable. The availability of high-resolution crystal structures (1.25 Å) and multiple PDB entries provide strong structural validation for rational drug design targeting allosteric or protein-protein interaction sites.

Mechanism: Small molecule modulator of transcriptional coactivator function

Drug Pipeline (3 compounds)

1 Approved · 2 Preclinical

Known Drugs:

Bezafibrate (approved) — PPAR agonist, indirectly activates PGC-1α, dyslipidemia

AICAR (investigational) — AMPK activator, upregulates PGC-1α expression

ZLN005 (preclinical) — Selective PGC-1α transcriptional activator

Structural Data:

PDB (7) ✓AlphaFold ✓Cryo-EM —

1XB7 3CS8 3D24 6LN4 8BF1+2 more

UniProt: Q9UBK2

🧬 3D Protein Structure

🧬 PPARGC1A — PDB 3CS8 Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity challenges include potential cross-reactivity with related coactivators (PGC-1β, PGC-1α4 isoforms) and off-target effects on broader PPAR signaling pathways when using indirect activators. Direct PGC-1α modulators like ZLN005 offer improved selectivity by targeting the transcriptional activation domain rather than upstream signaling cascades.

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

1

Completed

7

Total Enrollment

330

By Phase

NA: 2 · PHASE2: 3 · PHASE3: 2 · Unknown: 1

Bezafibrate in Patients With Primary Biliary Cholangitis (PBC) Recruiting

Unknown NCT04514965 n=100

Primary Biliary Cirrhosis

Interventions: Blood sampling, Fibroscan, Question

Sponsor: University of Aarhus | Started: 2020-10-01

Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis Completed

PHASE3 NCT01654731 n=100

PBC

Interventions: Bezafibrate, placebo

Sponsor: Assistance Publique - Hôpitaux de Paris | Started: 2012-10-15

Bezafibrate Plus Berberine in Mixed Dyslipidemia Completed

PHASE3 NCT02548832 n=36

Mixed Dyslipidemia

Interventions: Berberine, Bezafibrate, Berberine plus Bezafibrate

Sponsor: University of Guadalajara | Started: 2013-04

Effect of Bezafibrate on Muscle Metabolism in Patients With Fatty Acid Oxidation Defects Completed

PHASE2 NCT00983788 n=12

Carnitine Palmitoyltransferase II Defici, Very Long Chain Acyl Coa Dehydrogenase D

Interventions: Bezafibrate, Placebo

Sponsor: Rigshospitalet, Denmark | Started: 2009-10

A Study of Bezafibrate in Mitochondrial Myopathy Completed

PHASE2 NCT02398201 n=6

Mitochondrial Diseases

Interventions: Bezafibrate

Sponsor: Newcastle-upon-Tyne Hospitals NHS Trust | Started: 2015-09

Phase II Pilot Study of Aminoimidazole Carboxamide Riboside (AICAR), a Precursor of Purine Synthesis, for Lesch-Nyhan Di Completed

PHASE2 NCT00004314 n=2

Lesch-Nyhan Syndrome

Interventions: aminomidazole carboxamide riboside

Sponsor: National Center for Research Resources (NCRR) | Started: 1996-02

PC-300 Tea Effect on Triglyceride Levels Completed

NA NCT03649269 n=34

Hypertriglyceridemia

Interventions: PC-300 tea., Bezafibrate

Sponsor: Ciprés Grupo Médico CGM SC | Started: 2014-01-01

Contraction (Exercise) Mediated Glucose Uptake as a Therapeutic Target in Type 2 Diabetes Completed

NA NCT00168519 n=40

Diabetes Mellitus, Type 2

Interventions: nitroprusside, pentalong, imdur, AICAR,

Sponsor: Baker Heart Research Institute | Started: 2002-10

Linked Hypotheses (2)

Perforant Path Presynaptic Terminal Protection Strategy0.696

PGC1α Activation in PV+ Interneurons Bypasses Mitophagy Deficit to Restore Gamma Oscillations0.455

Linked Experiments (3)

PGC-1α knockout effects on PV+ interneuron maturation0.900

PGC-1α expression analysis during PV+ interneuron development0.800

Activity-dependent regulation of PGC-1α in PV+ interneurons0.800

Scoring Dimensions

Knowledge Graph (20)

associated with (1)

PPARGC1A→neurodegeneration

co discussed (17)

PPARGC1A→SLC16A2PPARGC1A→RELNPPARGC1A→MAP6PPARGC1A→HCN1PPARGC1A→MCU

▸ Show 12 more

PPARGC1A→IDH2FOXP3→PPARGC1ATNFA→PPARGC1APPARGC1A→NR3C1PPARGC1A→DRD2PPARGC1A→CHR2PPARGC1A→CLOCKPPARGC1A→CRHPPARGC1A→BDNFPPARGC1A→SNCAPPARGC1A→ANGPT1PPARGC1A→ULK1

interacts with (2)

PPARGC1A→PRKAA1PRKAA1→PPARGC1A

Debate History (1)

Should PPARGC1A (Peroxisome proliferator-activated receptor gamma coactivator 1-2026-04-21