NLRP3

NACHT, LRR and PYD domains-containing protein 3

Score: 0.637 Price: $0.64 Medium Druggability Status: active Wiki: NLRP3

🔥 Neuroinflammation 🧠 Neurodegeneration

HYPOTHESES

9

PAPERS

0

KG EDGES

2128

DEBATES

1

3D Protein Structure

🧬 NLRP3 — PDB 7LMZ Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.51

Clinical Stage

Approved

Target Class

Signaling Protein

Safety

0.50

Druggability Analysis

Drug Development0.75

Structural Tractability0.85

Target Class0.50

Safety Profile0.50

Key Metrics

PDB Structures:

25

Known Drugs:

2

Approved:

1

In Clinical Trials:

0

Drug Pipeline (2 compounds)

1 Approved · 1 Preclinical

Druggability Rationale: NLRP3 demonstrates medium druggability (0.55) supported by existing approved drugs (colchicine) and investigational candidates (MCC950), robust structural characterization (25 PDB structures, cryo-EM data), and well-defined inflammasome assembly mechanisms. However, achieving selective NLRP3 inhibition without broad immunosuppression remains challenging, as the target is a large multi-domain signaling scaffold rather than a classical enzyme active site.

Mechanism: Small molecule inhibitors targeting NLRP3 inflammasome assembly or activation

Drug Pipeline (2 compounds)

1 Approved · 1 Preclinical

Known Drugs:

MCC950 (investigational) — inflammatory diseases

Colchicine (approved) — gout, pericarditis

Structural Data:

PDB (25) ✓AlphaFold ✓Cryo-EM ✓

2NAQ 6NPY 7ALV 7LFH 7PZC+20 more

UniProt: A0A7I2R3P8

🧬 3D Protein Structure

🧬 NLRP3 — PDB 7LMZ Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

NLRP3 selectivity is critical as off-target inhibition of related inflammasomes (NLRC4, AIM2) or broader NLR family members could impair protective immunity. Achieving selectivity is complicated by homologous NACHT and LRR domain architecture across the NLR family, though allosteric inhibitors targeting NLRP3-specific conformational states offer improved selectivity over direct competitive approaches.

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

4

Completed

4

Total Enrollment

445

By Phase

PHASE1: 2 · PHASE2: 3 · PHASE3: 1 · PHASE4: 2

Colchicine's Effect on Inflammatory Markers Recruiting

PHASE4 NCT07287345 n=24

Colchicine, Inflammation in Cardiac Surgery, Post Operative Atrial Fibrillation

Interventions: Colchicine (Colcrys®), Placebo

Sponsor: Ayesha Ather | Started: 2026-01-16

Colchicine to Quench the Inflammatory Response After Deep Vein Thrombosis (The Conquer-DVT Pilot Trial) Recruiting

PHASE3 NCT06440694 n=150

Venous Thromboembolism

Interventions: Colchicine 0.5 mg po, Placebo 0.5 mg po

Sponsor: Ottawa Hospital Research Institute | Started: 2025-07-07

A Trial to Test the Use of Dapansutrile, an Anti-inflammatory Medication, in People With Parkinson's Disease Recruiting

PHASE2 NCT07157735 n=36

Parkinson Disease

Interventions: dapansutrile, placebo

Sponsor: Cambridge University Hospitals NHS Foundation Trust | Started: 2026-02-02

First-in-Human Single and Multiple Dose of HL-400 Recruiting

PHASE1 NCT06997484 n=54

Parkinson Disease

Interventions: HL-400, Placebo

Sponsor: Highlightll Pharmaceutical (USA) LLC | Started: 2025-04-25

Anti-platelet Effects of Colchicine in Healthy Volunteers Completed

PHASE4 NCT02140372 n=10

Healthy

Interventions: Colchicine

Sponsor: NYU Langone Health | Started: 2014-05

Open Label Safety/Efficacy Study of Arhalofenate in Combination With Febuxostat for Hyperuricemia in Gout Patients Completed

PHASE2 NCT01416402 n=27

Hyperuricemia, Gout

Interventions: Arhalofenate, Febuxostat, Colchicine

Sponsor: Gilead Sciences | Started: 2011-08

Safety and Efficacy Study of MBX-102 in Treatment of Hyperuricemia in Patients With Gout Completed

PHASE2 NCT01336686 n=67

Hyperuricemia, Gout

Interventions: Arhalofenate, Arhalofenate, Placebo comparator

Sponsor: Gilead Sciences | Started: 2011-05

Effects of Colchicine in Non-Diabetic Adults With Metabolic Syndrome Completed

PHASE1 NCT02153983 n=77

Obesity, Metabolic Disease

Interventions: Colchicine 0.6Mg Cap, Placebo capsules given, Colchicine 0.6Mg Tab

Sponsor: Eunice Kennedy Shriver National Institute of Child Health an | Started: 2014-05-31

Linked Hypotheses (8)

NLRP3/Mitophagy Coupling Modulation0.681

NLRP3 Inflammasome Inhibition Prevents Synapse Loss via IL-1β Suppression0.610

Intermittent HBOT (2.0 ATA, 60 min, 3x/week) suppresses NLRP3 inflammasome and shifts microglial pol0.590

NLRP3 Inflammasome Chromatin Priming Through H3K27ac Accumulation0.566

NLRP3 Inflammasome Blockade as Upstream Intervention to Prevent SASP Amplification0.566

Temporal NLRP3 Inhibition During SPP1-Driven Microglial Activation Windows0.551

Temporal NLRP3 Inhibition via SPP1-Mediated Mitophagy Enhancement During Critical Neuroinflammatory 0.496

Compensatory Cytokine Network Activation0.455

Linked Experiments (4)

Molecular characterization of RBG-NLRP3 binding interaction0.900

RBG effects on macrophage polarization and foam cell formation0.850

Transcriptomic analysis of RBG effects on inflammatory gene expression0.800

NLRP3 Inflammasome Validation Study in Parkinson's Disease0.400

Scoring Dimensions

Knowledge Graph (20)

component of (1)

NLRP3→inflammasome_complex

interacts with (19)

NLRP3→CASP1NLRP3→IL1BNLRP3→PYCARDCASP1→NLRP3IL1B→NLRP3

▸ Show 14 more

PYCARD→NLRP3CAT→NLRP3OPTN→NLRP3DNM1L→NLRP3CANX→NLRP3LGALS3→NLRP3CALCOCO2→NLRP3G3BP1→NLRP3PEX3→NLRP3SQSTM1→NLRP3BCL2→NLRP3LMNA→NLRP3STING1→NLRP3TAX1BP1→NLRP3

Debate History (1)

Should NLRP3 (NACHT, LRR and PYD domains-containing protein 3) be prioritized as2026-04-21