KCNK2

Potassium two pore domain channel subfamily K member 2

Score: 0.667 Price: $0.67 Medium Druggability Status: active Wiki: KCNK2

🧠 Neurodegeneration

HYPOTHESES

2

PAPERS

55

KG EDGES

293

DEBATES

1

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:

26

Known Drugs:

5

Approved:

4

In Clinical Trials:

0

Drug Pipeline (5 compounds)

4 Approved · 1 Preclinical

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

🧬 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.

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

3

Completed

5

Total Enrollment

1,363

By Phase

NA: 1 · PHASE1: 4 · PHASE3: 1 · PHASE4: 1 · Unknown: 1

Predicting Treatment Outcomes in Refractory Constipation Through Brain Connectivity Evaluation Recruiting

Unknown NCT06221722 n=150

Constipation - Functional, Refractory Constipation, Fluoxetine

Interventions: BOLD-fMRI, Regular treatment of functional constipa, fluoxetine

Sponsor: Xijing Hospital of Digestive Diseases | Started: 2023-11-01

Evaluation of Fluoxetine for Refractory Constipation With Somatic Symptom Disorder Features Not Yet Recruiting

PHASE1 NCT06506136 n=194

Refractory Constipation, Somatic Symptom Disorder (DSM-5), Functional Constipation (FC)

Interventions: Fluoxetine, Placebo

Sponsor: Zhifeng Zhao, PhD | Started: 2025-09-01

Assessment of PENG Block as a Part of Multimodal Analgesia Following Hip Surgeries. Active Not Recruiting

NA NCT06916000 n=50

Anesthesia

Interventions: Pericapsular nerve group (PENG) block, Patients will receive only other multimo

Sponsor: Ain Shams University | Started: 2024-06-27

A Comparison of Antiarrhythmic Drug Therapy and Radio Frequency Catheter Ablation in Patients With Paroxysmal Atrial Fib Completed

PHASE4 NCT00540787 n=112

Paroxysmal Atrial Fibrillation

Interventions: Radiofrequency ablation, antiarrhythmic , Amiodarone, flecainide, propafenone, qui, ThermoCool Radiofrequency Catheter

Sponsor: Biosense Webster, Inc. | Started: 2003-08-01

Assessment of the Efficacy, Safety, and Tolerability of AVP-786 (Deudextromethorphan Hydrobromide [d6-DM]/Quinidine Sulf Completed

PHASE3 NCT03393520 n=601

Agitation in Patients With Dementia of t

Interventions: Placebo, AVP-786

Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Started: 2017-10-13

A Study of the Effect of Multiple Doses of Itraconazole and Fluoxetine on the Pharmacokinetics of a Single Dose of RO528 Completed

PHASE1 NCT01967979 n=28

Healthy Volunteer

Interventions: RO5285119, fluoxetine, itraconazole

Sponsor: Hoffmann-La Roche | Started: 2013-10

Study in Healthy Volunteers to Investigate the Effects of Quinidine on the Pharmacokinetics of NKTR-118 Completed

PHASE1 NCT01533155 n=214

Drug Induced Constipation

Interventions: Nektar 118, Quinidine, Quinidine placebo

Sponsor: AstraZeneca | Started: 2012-03

A Study to Investigate the Effect of Food on Balcinrenone/Dapagliflozin Pharmacokinetics in Fed and Fasted State and Pha Completed

PHASE1 NCT06979388 n=14

Healthy Participants

Interventions: balcinrenone/ dapagliflozin, quinidine

Sponsor: AstraZeneca | Started: 2025-05-20

Linked Hypotheses (1)

Aquaporin-4 Polarization Enhancement via TREK-1 Channel Modulation0.668

Linked Experiments (0)

No linked experiments

Scoring Dimensions

Knowledge Graph (20)

associated with (1)

KCNK2→neurodegeneration

co discussed (17)

BMAL1→KCNK2HK2→KCNK2MIRO1→KCNK2P2RY1→KCNK2SOAT1→KCNK2

▸ Show 12 more

KCNK2→TET2KCNK2→PIEZO1KCNK2→P2RX7KCNK2→DGAT1KCNK2→C3AQP1→KCNK2KCNK2→GJA1KCNK2→HCRTR2KCNK2→LOXL1-4KCNK2→HCRTR1KCNK2→AQP4KCNK2→LOX

interacts with (2)

PIEZO1→KCNK2KCNK2→PIEZO1

Debate History (1)

Should KCNK2 (Potassium two pore domain channel subfamily K member 2) be priorit2026-04-21