KCNK2

Potassium two pore domain channel subfamily K member 2

Score: 0.730 Price: $0.73 Medium Druggability Status: active Wiki: KCNK2

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

293

DEBATES

3D Protein Structure

🧬 KCNK2 — PDB 6CIR Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.58

Clinical Stage

Approved

Target Class

Ion Channel

Safety

0.50

Druggability Analysis

Drug Development1.00

Structural Tractability0.85

Target Class0.85

Safety Profile0.50

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (5 compounds)

4 Approved · 1 Preclinical

Therapeutic Areas:

Neurodegenerative diseases (Alzheimer's, Parkinson's) Neuropathic pain Depression and anxiety disorders Epilepsy and seizure disorders Stroke and ischemic neuroprotection Sleep disorders

Druggability Rationale: KCNK2 (TREK-1) represents a highly promising druggable target for neurodegeneration, with existing small molecule modulators demonstrating potential neuroprotective mechanisms. The structural resolution and multiple known pharmacological agents like fluoxetine and quinidine suggest a robust opportunity for targeted intervention, particularly given the potassium channel's role in neuronal excitability and potential neuroprotective signaling. The availability of high-resolution structural data and multiple existing compounds provides a strong foundation for further neurotherapeutic development.

Mechanism: KCNK2 encodes a two-pore domain potassium channel (TREK-1) that regulates neuronal excitability, membrane potential, and cellular responsiveness to mechanical and chemical stimuli in the central nervous system. In neurodegeneration, TREK-1 modulation can influence neuronal survival, mitochondrial function, and potentially mitigate oxidative stress and excitotoxicity through precise potassium conductance regulation.

Drug Pipeline (5 compounds)

4 Approved · 1 Preclinical

Known Drugs:

Fluoxetine (approved)

Halothane (approved)

Quinidine (approved)

Bupivacaine (approved)

ML335 (preclinical)

Structural Data:

PDB (26) ✓AlphaFold ✓Cryo-EM —

4TWK 6CQ6 6CQ8 6CQ9 6W7B+21 more

UniProt: C9JXY2

Binding Pocket Analysis:

KCNK2 features a conserved interfacial ligand-binding pocket located between the inner and outer transmembrane helices, accessible to small molecules in both open and closed conformational states. The binding site accommodates diverse chemical scaffolds (evidenced by fluoxetine, local anesthetics, and antiarrhythmics), suggesting an allosteric modulation mechanism rather than a canonical orthosteric site, enabling both positive and negative modulatory effects.

🧬 3D Protein Structure

🧬 KCNK2 — PDB 6CIR Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity represents a significant challenge given KCNK2's structural homology to other K2P family members (KCNK1, KCNK3, KCNK4), which share similar pharmacophores and binding architectures. Off-target activity on related K2P channels could lead to unexpected cardiovascular or respiratory effects; ML335 and next-generation modulators must be carefully profiled against the full K2P subfamily to ensure isoform selectivity.