KCNK3

Summary

KCNK3 (potassium two pore domain channel subfamily K member 3, HGNC:6278) is a protein-coding gene on chromosome 2p23.3, encoding Potassium channel subfamily K member 3 (O14649). K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.

This gene encodes a member of the superfamily of potassium channel proteins that contain two pore-forming P domains. The encoded protein is an outwardly rectifying channel that is sensitive to changes in extracellular pH and is inhibited by extracellular acidification. Also referred to as an acid-sensitive potassium channel, it is activated by the anesthetics halothane and isoflurane. Although three transcripts are detected in northern blots, there is currently no sequence available to confirm transcript variants for this gene.

Source: NCBI Gene 3777 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary arterial hypertension (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 80
• Clinical variants (ClinVar): 295 total — 12 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 67
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002246

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6278
Approved symbol	KCNK3
Name	potassium two pore domain channel subfamily K member 3
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	K2p3.1, TASK, TASK-1, TASK1
Ensembl gene	ENSG00000171303
Ensembl biotype	protein_coding
OMIM	603220
Entrez	3777

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000302909

RefSeq mRNA: 1 — MANE Select: NM_002246 NM_002246

CCDS: CCDS1727

Canonical transcript exons

ENST00000302909 — 2 exons

Exon	Start	End
ENSE00001136405	26727667	26733420
ENSE00001136410	26692722	26693158

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 98.15.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6877 / max 214.6224, expressed in 329 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19272	1.0358	264
19271	0.3775	169
19273	0.1622	72
19270	0.1122	57

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland	UBERON:0001234	98.15	gold quality
adrenal cortex	UBERON:0001235	98.11	gold quality
left adrenal gland cortex	UBERON:0035825	98.04	gold quality
right adrenal gland cortex	UBERON:0035827	98.00	gold quality
right adrenal gland	UBERON:0001233	97.99	gold quality
adrenal gland	UBERON:0002369	96.59	gold quality
type B pancreatic cell	CL:0000169	94.03	gold quality
lower lobe of lung	UBERON:0008949	92.00	gold quality
right lung	UBERON:0002167	91.69	gold quality
islet of Langerhans	UBERON:0000006	88.85	gold quality
adrenal tissue	UBERON:0018303	87.91	gold quality
paraflocculus	UBERON:0005351	87.23	gold quality
pons	UBERON:0000988	87.05	gold quality
upper lobe of lung	UBERON:0008948	86.36	gold quality
upper lobe of left lung	UBERON:0008952	85.80	gold quality
pancreas	UBERON:0001264	85.69	gold quality
cerebellar vermis	UBERON:0004720	85.65	gold quality
body of pancreas	UBERON:0001150	85.56	gold quality
decidua	UBERON:0002450	85.01	gold quality
placenta	UBERON:0001987	84.71	gold quality
lung	UBERON:0002048	84.69	gold quality
frontal pole	UBERON:0002795	84.05	gold quality
superior vestibular nucleus	UBERON:0007227	82.74	gold quality
lateral nuclear group of thalamus	UBERON:0002736	82.34	gold quality
right atrium auricular region	UBERON:0006631	81.09	gold quality
cardiac atrium	UBERON:0002081	80.56	gold quality
right coronary artery	UBERON:0001625	80.53	gold quality
urethra	UBERON:0000057	79.95	gold quality
Brodmann (1909) area 10	UBERON:0013541	79.89	gold quality
left coronary artery	UBERON:0001626	79.24	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.67

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1B, HNF4A

miRNA regulators (miRDB)

121 targeting KCNK3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-2110	99.96	66.68	1930

Literature-anchored findings (GeneRIF, showing 40)

• TASK-1 and TASK-3 differed insofar as a large portion of the C terminus was necessary for the full effects of halothane and TRH on TASK-3 but not on TASK-1 (PMID:11886861)
• Renal Oat1 expression gradually increased throughout development, approaching adult levels at 30 days of age, where at days 40 and 45 Oat1 levels were greater in males than females (PMID:11907168)
• C-PAF blocks TASK-1 or a closely related channel, the effect is PKC dependent, and the inhibition alters the electrical activity of myocytes in ways that would be arrhythmogenic in the intact heart. (PMID:12003807)
• Association with p11 is essential for trafficking of TASK-1 to the plasma membrane. This association masks an ER retention signal identified as Lys-Arg-Arg that precedes the Ser-Ser-Val sequence. (PMID:12198146)
• KCNK3 potassium channels are shown to bear two cytoplasmic trafficking motifs: an N-terminal dibasic site that binds beta-COP to hold channels in ER and a C-terminal “release” site that binds the ubiquitous intracellular regulator 14-3-3beta (PMID:12437930)
• hOAT1-expressing cell line showed extensive para-aminohippuric acid transport. hOAT1 also demonstrated 1:1 coupling between organic anion and dicarboxylate. (PMID:12837685)
• Host TASK-1 protein and HIV-1 Vpu undergo mutual functional destruction. (PMID:15099524)
• TASK1 is expressed in pia mater, astrocytes, Purkinje and granule cells (PMID:15197476)
• Human cytotrophoblast cells from term placenta are a site of expression for various K2P genes, two of which, namely, TASK1 and TREK1, are transcribed into protein. (PMID:15695101)
• TASK-1 is hypoxia-sensitive and controls the resting membrane potential, thus implicating an important role for TASK-1 K+ channels in the regulation of pulmonary vascular tone. (PMID:16574908)
• the role of TASK channels in sensing physiological stimuli. (PMID:17945357)
• K(2)P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders (PMID:18375952)
• Thus, regulated expression of TASK channels might contribute to a molecular switch between death and survival of neurons in autoimmune CNS inflammation. (PMID:18824070)
• ET-1 depolarized human primary pulmonary artery smooth muscle cells by phosphorylating TASK-1. This effect was abrogated by TASK-1 siRNA. This might represent a novel pathologic mechanism related to pulmonary arterial hypertension. (PMID:19188660)
• O2 binding with NOX4 per se controls TASK-1 activity. In this process, the heme moiety and FBD seem to be responsible for the NOX4 regulation of TASK-1, and p22 might support the NOX4-TASK-1 interaction (PMID:19657056)
• TASK-1 and 3 are determinant of aldosterone secretion and adrenocortical zonation. (PMID:20049674)
• Western analysis confirms expression of TASK1 and TASK3 in medulloblastoma cells. (PMID:20931182)
• cAMP-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both K(2P)3.1 and K(2P)9.1 (PMID:21357689)
• analysis of how the specific two-pore domain potassium channel blocker A1899 defines the structure of the TASK-1 open pore (PMID:21362619)
• TASK-1- and TASK-3-mediated currents are not affected by depletion of plasma membrane PI4,5P2 either via the voltage-activated phosphatase Ci-VSP or via chemically triggered recruitment of a PI4,5P2-5’-phosphatase. (PMID:21540350)
• TASK-1 immunoreactivity was observed in astrocytes of temporal lobe epilepsy patients. (PMID:21710317)
• ET-1 inhibited TASK1-mediated I(KN) currents in hPASMC. (PMID:21838752)
• I(TASK-1) contributes to the sustained outward current I(Ksus) and that I(TASK-1) is a major component of the background conductance in human atrial cardiomyocytes. (PMID:22178873)
• There were no associations between KCNK3 single nucleotide polymorphisms and blood pressure or aldosterone production. (PMID:22893713)
• TASK-1 suppresses HIV-1 replication. (PMID:23164059)
• Ability to induce atrial fibrillation in the peri-operative period is associated with phosphorylation-dependent inhibition of TWIK protein-related acid-sensitive potassium channel 1 (PMID:23229553)
• TASK and TREK-1 are involved in regulation of cell proliferation and in control of resting membrane potentials in endometrial epithelial cells. (PMID:23305490)
• K2P3.1 and K2P9.1 undergo rapid dynamin-dependent endocytosis (PMID:23807092)
• Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. (PMID:23883380)
• Sec61 complex reorientation of the first signal-anchor sequence of TASK-1 determines membrane topology of the other membrane spanning regions. (PMID:24015703)
• demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate (PMID:24374141)
• Syntaxin-8 regulates the endocytosis of TASK-1. (PMID:24743596)
• A glucose-dependent role for beta-cell TASK-1 channels of limiting glucose-stimulated Deltapsip depolarization and insulin secretion, which modulates glucose homeostasis. (PMID:24932805)
• Diacylglycerol mediates regulation of TASK1 and TASK3 potassium channels by GNAQ. (PMID:25420509)
• TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes. (PMID:25655935)
• Enhancement of atrium-selective K(2P)3.1 currents contributes to action potential shortening in atrial fibrillation patients. (PMID:25951834)
• control of TASK-1 trafficking by COPI, kinases, phosphatases and 14-3-3 proteins is highly dynamic. (PMID:26743085)
• Functional alanine-mutagenesis screens of TASK-1 and TRAAK were used to build an in silico model of the TASK-1 cap. (PMID:26794006)
• KCNK3 expression and function were reduced in pulmonary artery smooth muscle cells and endothelial cells in human pulmonary arterial hypertension. (PMID:26912814)
• Knockdown of TASK-1 by siRNA significantly enhanced apoptosis and reduced proliferation in Non-Small Cell Lung Cancer A549 cells, but not in weakly TASK-1 expressing NCI-H358 cells. (PMID:27294516)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnk3a	ENSDARG00000043466
danio_rerio	kcnk3b	ENSDARG00000052898
mus_musculus	Kcnk3	ENSMUSG00000049265
rattus_norvegicus	Kcnk3	ENSRNOG00000009790
drosophila_melanogaster	Task7	FBGN0037690
drosophila_melanogaster	Task6	FBGN0038165
drosophila_melanogaster	CG10864	FBGN0038621
drosophila_melanogaster	CG42340	FBGN0259242
caenorhabditis_elegans		WBGENE00006661
caenorhabditis_elegans		WBGENE00006674
caenorhabditis_elegans		WBGENE00006675
caenorhabditis_elegans		WBGENE00006679
caenorhabditis_elegans		WBGENE00006685
caenorhabditis_elegans		WBGENE00006686
caenorhabditis_elegans		WBGENE00006695
caenorhabditis_elegans		WBGENE00006696

Paralogs (14): KCNK2 (ENSG00000082482), KCNK16 (ENSG00000095981), KCNK6 (ENSG00000099337), KCNK10 (ENSG00000100433), KCNK15 (ENSG00000124249), KCNK17 (ENSG00000124780), KCNK1 (ENSG00000135750), KCNK13 (ENSG00000152315), KCNK5 (ENSG00000164626), KCNK9 (ENSG00000169427), KCNK7 (ENSG00000173338), KCNK4 (ENSG00000182450), KCNK12 (ENSG00000184261), KCNK18 (ENSG00000186795)

Protein

Protein identifiers

Potassium channel subfamily K member 3 — O14649 (reviewed: O14649)

Alternative names: Acid-sensitive potassium channel protein TASK-1, TWIK-related acid-sensitive K(+) channel 1, Two pore potassium channel KT3.1

All UniProt accessions (1): O14649

UniProt curated annotations — full annotation on UniProt →

Function. K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an ‘ion flux gating’ mode where outward but not inward ion flow opens the gate. Changes ion selectivity and becomes permeable to Na(+) ions in response to extracellular acidification. Protonation of the pH sensor His-98 stabilizes C-type inactivation conformation likely converting the channel from outward K(+)-conducting, to inward Na(+)-conducting to nonconductive state. Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties. Allows K(+) currents with fast-gating kinetics important for the repolarization and hyperpolarization phases of action potentials. In cerebellar granule cells, heteromeric KCNK3:KCNK9 channel may hyperpolarize the resting membrane potential to limit intrinsic neuronal excitability, but once the action potential threshold is reached, it may support high-frequency action potential firing and increased neuronal excitability. Dispensable for central chemosensory respiration i.e. breathing controlled by brainstem CO2/pH, it rather conducts pH-sensitive currents and controls the firing rate of serotonergic raphe neurons involved in potentiation of the respiratory chemoreflex. Additionally, imparts chemosensitivity to type 1 cells in carotid bodies which respond to a decrease in arterial oxygen pressure or an increase in carbon dioxide pressure or pH to initiate adaptive changes in pulmonary ventilation. In adrenal gland, contributes to the maintenance of a hyperpolarized resting membrane potential of aldosterone-producing cells at zona glomerulosa and limits aldosterone release as part of a regulatory mechanism that controls arterial blood pressure and electrolyte homeostasis. In brown adipocytes, mediates K(+) efflux that counteracts norepinephrine-induced membrane depolarization, limits Ca(2+) efflux and downstream cAMP and PKA signaling, ultimately attenuating lipid oxidation and adaptive thermogenesis.

Subunit / interactions. Homodimer. Heterodimer with KCNK1. Heterodimer with KCNK9. Interacts with SERTM2; the interaction may affect the resting potential of neurons.

Subcellular location. Cell membrane.

Tissue specificity. Widespread expression in adult. Strongest expression in pancreas and placenta. Lower expression in brain, lung, prostate, heart, kidney, uterus, small intestine and colon.

Disease relevance. Pulmonary hypertension, primary, 4 (PPH4) [MIM:615344] A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. The disease is caused by variants affecting the gene represented in this entry. Defects in this gene may cause developmental delay with sleep apnea (DDSA). A disorder characterized by developmental neurologic, skeletal and respiratory anomalies including microcephaly, arthrogryposis, scoliosis, cleft palate, facial dysmorphology, bilateral talipes, feeding difficulties and central and/or obstructive sleep apnea. Malformations are detected as early as 21 weeks post gestation. Severely affected patients require ongoing treatment with nocturnal O2 or pressure-controlled ventilation. The disease is associated with recurrent de novo gain of function variants.

Activity regulation. Inhibited by external acidification, diacylglycerol and anandamide. Activated by halothane and isoflurane.

Domain organisation. Each subunit contributes two pore-forming domains 1 and 2 which assemble to form a single pore with M2 and M4 transmembrane helices lining the central cavity and M1 and M3 facing the lipid bilayer. The transmembrane helices are bridged by the selectivity filters 1 and 2 carrying a signature sequence TxTTxG(Y/F)G(D/H) that coordinate the permeant ions. Up to four ions can simultaneously occupy the selectivity filter and at least two elementary charges must translocate across the filter to convert it into the open conformation. The X-gate is positioned at the distal ends of M4 transmembrane helices forming a two-turn-helical structure with the methyl group of Thr-248 closing the ion conduction pathway.

Similarity. Belongs to the two pore domain potassium channel (TC 1.A.1.8) family.

RefSeq proteins (1): NP_002237* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003092	2pore_dom_K_chnl_TASK	Family
IPR003280	2pore_dom_K_chnl	Family
IPR005406	KCNK3	Family
IPR013099	K_chnl_dom	Domain

Pfam: PF07885

Catalyzed reactions (Rhea), 2 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (99 total): mutagenesis site 43, binding site 14, sequence variant 13, helix 11, region of interest 5, transmembrane region 4, topological domain 3, intramembrane region 2, chain 1, compositionally biased region 1, glycosylation site 1, strand 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6RV3	X-RAY DIFFRACTION	2.9
6RV2	X-RAY DIFFRACTION	3
6RV4	X-RAY DIFFRACTION	3.1
9G9X	ELECTRON MICROSCOPY	3.13

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14649-F1	76.07	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (14): 93; 93; 94; 94; 95; 95; 96; 199; 199; 200; 200; 201 …

Glycosylation sites (1): 53

Mutagenesis-validated functional residues (43):

Position	Phenotype
4	increases potassium current amplitude.
5	increases potassium current amplitude.
6	no effect on channel basal activity.
7	increases potassium current amplitude.
7	no effect on channel basal activity.
8	no effect on channel basal activity.
98	greatly reduces ph sensitivity.
130	no effect on channel basal activity.
131	increases potassium current amplitude.
132	no effect on channel basal activity.
133	increases potassium current.
133	increases potassium current amplitude.
134	no effect on channel basal activity.
199	abolishes voltage gating. conducts currents with linear i-v relationship characteristic of classical leak channels.
230	no effect on channel basal activity.
231	no effect on channel basal activity.
232	no effect on channel basal activity.
233	no effect on channel basal activity.
234	no effect on channel basal activity.
235	no effect on channel basal activity.
236	no effect on channel basal activity.
237	increases potassium current amplitude.
238	no effect on channel basal activity.
239	no effect on channel basal activity.
240	no effect on channel basal activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1299316	TWIK-releated acid-sensitive K+ channel (TASK)
R-HSA-5576886	Phase 4 - resting membrane potential
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-1296346	Tandem pore domain potassium channels
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 199 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, BENPORATH_ES_WITH_H3K27ME3, GOBP_RESPONSE_TO_ZINC_ION, MODULE_274, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_TANDEM_PORE_DOMAIN_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, PEREZ_TP63_TARGETS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, MODULE_45, MODULE_64, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (16): detection of hypoxic conditions in blood by carotid body chemoreceptor signaling (GO:0003029), potassium ion transport (GO:0006813), chemical synaptic transmission (GO:0007268), response to xenobiotic stimulus (GO:0009410), monoatomic ion transmembrane transport (GO:0034220), negative regulation of cytosolic calcium ion concentration (GO:0051481), regulation of resting membrane potential (GO:0060075), cellular response to zinc ion (GO:0071294), cellular response to hypoxia (GO:0071456), cellular response to acidic pH (GO:0071468), potassium ion transmembrane transport (GO:0071805), cochlea development (GO:0090102), regulation of action potential firing rate (GO:0099605), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), sodium ion transmembrane transport (GO:0035725)

GO Molecular Function (10): monoatomic ion channel activity (GO:0005216), open rectifier potassium channel activity (GO:0005252), potassium channel activity (GO:0005267), sodium channel activity (GO:0005272), outward rectifier potassium channel activity (GO:0015271), potassium ion leak channel activity (GO:0022841), S100 protein binding (GO:0044548), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), synapse (GO:0045202), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Tandem pore domain potassium channels	1
Cardiac conduction	1
Neuronal System	1
Potassium Channels	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	2
monoatomic cation transmembrane transport	2
voltage-gated potassium channel activity	2
monoatomic cation channel activity	2
detection of hypoxic conditions in blood by chemoreceptor signaling	1
regulation of systemic arterial blood pressure by carotid body chemoreceptor signaling	1
anterograde trans-synaptic signaling	1
response to chemical	1
monoatomic ion transport	1
transmembrane transport	1
regulation of biological quality	1
regulation of membrane potential	1
response to zinc ion	1
cellular response to metal ion	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
response to acidic pH	1
cellular response to pH	1
potassium ion transport	1
inner ear development	1
anatomical structure development	1
regulation of action potential	1
transport	1
sodium ion transport	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
potassium ion transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
potassium channel activity	1
leak channel activity	1
protein binding	1
cation binding	1
protein dimerization activity	1
binding	1
membrane	1
cell periphery	1
cell junction	1
cellular anatomical structure	1

Protein interactions and networks

STRING

914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNK3	S100A10	P08206	943
KCNK3	KRT76	Q01546	878
KCNK3	KCNK9	Q9NPC2	862
KCNK3	SCN10A	Q9Y5Y9	750
KCNK3	ANXA2	P07355	737
KCNK3	GABRD	O14764	716
KCNK3	KCNA5	P22460	705
KCNK3	BMPR2	Q13873	692
KCNK3	ACVRL1	P37023	673
KCNK3	ATP13A3	Q9H7F0	652
KCNK3	SMAD9	O15198	645
KCNK3	KCNS1	Q96KK3	636
KCNK3	TBX4	P57082	629
KCNK3	KCNK5	O95279	626
KCNK3	KCNK1	O00180	617

IntAct

11 interactions, top by confidence:

A	B	Type	Score
YWHAB	KCNK3	psi-mi:“MI:0407”(direct interaction)	0.670
YWHAB	KCNK3	psi-mi:“MI:0915”(physical association)	0.670
Ywhab	KCNK3	psi-mi:“MI:0914”(association)	0.460
KCNK3	KCNK3	psi-mi:“MI:0407”(direct interaction)	0.440
KCNK3	UBA52	psi-mi:“MI:0915”(physical association)	0.400
PHACTR3	KCNK3	psi-mi:“MI:0914”(association)	0.350
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (9): KCNK3 (Affinity Capture-MS), UBA52 (Proximity Label-MS), KCNK3 (Two-hybrid), S100A10 (Reconstituted Complex), KCNK3 (Protein-peptide), YWHAB (Affinity Capture-Western), COPB1 (Affinity Capture-Western), COPB1 (Affinity Capture-Western), YWHAB (Affinity Capture-Western)

ESM2 similar proteins: A0A1D8PTL7, A2WNZ9, A2XVN3, A2YA15, A2YGP9, A3AVP1, O14649, O35111, O54912, O76819, P0C550, P14773, P28584, P47946, P92960, Q04400, Q0C8L9, Q0D9S3, Q0DWC7, Q0JKV1, Q0JNB6, Q0JPT5, Q10065, Q3LS21, Q3S2U3, Q4VY51, Q53JI9, Q54DA4, Q5GA22, Q5N941, Q5SML4, Q653P0, Q6H501, Q6RHR6, Q6T5K2, Q75HP9, Q75IS2, Q7PC71, Q7XPF7, Q7XPF8

Diamond homologs: G3V8R8, G3V8V5, G5E845, O00180, O08581, O14649, O17185, O35111, O54912, O88454, O95069, O95279, P57789, P97438, Q0P5A0, Q23435, Q3LS21, Q3TBV4, Q5RD07, Q5UE96, Q5VSE6, Q63ZI0, Q6Q1P3, Q6VV64, Q7Z418, Q8BUW1, Q8R454, Q8R5I0, Q920B6, Q96T54, Q96T55, Q9ERS1, Q9ES08, Q9H427, Q9HB14, Q9HB15, Q9JIS4, Q9JL58, Q9NPC2, Q9NYG8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
PRKACA	“up-regulates activity”	KCNK3	phosphorylation
RPS6KA3	“up-regulates activity”	KCNK3	phosphorylation
ROCK1	down-regulates	KCNK3	phosphorylation
ROCK1	“up-regulates activity”	KCNK3	phosphorylation
halothane	“up-regulates activity”	KCNK3	“chemical activation”
PRKCE	“down-regulates activity”	KCNK3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

295 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	3
Uncertain significance	169
Likely benign	97
Benign	6

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1204367	NM_002246.3(KCNK3):c.398A>G (p.Asn133Ser)	Pathogenic
2446440	NM_002246.3(KCNK3):c.607G>C (p.Gly203Arg)	Pathogenic
426049	NM_002246.3(KCNK3):c.23C>A (p.Thr8Lys)	Pathogenic
4526683	KCNK3, LEU122VAL	Pathogenic
4526684	KCNK3, LEU122PRO	Pathogenic
4526685	G129D	Pathogenic
4526686	KCNK3, ASN133SER	Pathogenic
4526687	KCNK3, LEU239PRO	Pathogenic
4526688	KCNK3, LEU241PHE	Pathogenic
60479	NM_002246.3(KCNK3):c.608G>A (p.Gly203Asp)	Pathogenic
60481	NM_002246.3(KCNK3):c.661G>C (p.Val221Leu)	Pathogenic
60483	NM_002246.3(KCNK3):c.575A>G (p.Tyr192Cys)	Pathogenic
548009	NM_002246.3(KCNK3):c.365T>C (p.Leu122Pro)	Likely pathogenic
60482	NM_002246.3(KCNK3):c.544G>A (p.Glu182Lys)	Likely pathogenic
813010	NM_002246.3(KCNK3):c.544G>C (p.Glu182Gln)	Likely pathogenic

SpliceAI

256 predictions. Top by Δscore:

Variant	Effect	Δscore
2:26693155:ATCGG:A	donor_loss	1.0000
2:26693157:CGGT:C	donor_loss	1.0000
2:26693158:GGTA:G	donor_loss	1.0000
2:26693159:G:GG	donor_gain	1.0000
2:26693159:GT:G	donor_loss	1.0000
2:26693160:T:G	donor_loss	1.0000
2:26727656:C:G	acceptor_gain	0.9900
2:26727665:A:AG	acceptor_gain	0.9900
2:26727666:G:GG	acceptor_gain	0.9900
2:26727655:A:AG	acceptor_gain	0.9800
2:26727663:CCAGG:C	acceptor_loss	0.9800
2:26727664:CAG:C	acceptor_loss	0.9800
2:26727665:A:AT	acceptor_loss	0.9800
2:26727666:G:A	acceptor_loss	0.9800
2:26727665:AG:A	acceptor_gain	0.9700
2:26727666:GG:G	acceptor_gain	0.9700
2:26727666:GGCT:G	acceptor_gain	0.9700
2:26693156:TCG:T	donor_gain	0.9600
2:26727666:GGC:G	acceptor_gain	0.9600
2:26727666:GGCTA:G	acceptor_gain	0.9400
2:26693155:ATCG:A	donor_gain	0.8900
2:26733292:T:TA	acceptor_gain	0.8600
2:26693161:A:C	donor_loss	0.7300
2:26694573:G:GT	donor_gain	0.7200
2:26724491:A:AG	donor_gain	0.7200
2:26693154:CATCG:C	donor_gain	0.7100
2:26693157:CG:C	donor_gain	0.6900
2:26693158:GG:G	donor_gain	0.6900
2:26699459:A:AG	donor_gain	0.6900
2:26693166:C:T	donor_gain	0.6600

AlphaMissense

2547 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:26692931:T:C	L19P	1.000
2:26692939:G:C	G22R	1.000
2:26692940:G:A	G22D	1.000
2:26693107:T:A	W78R	1.000
2:26693107:T:C	W78R	1.000
2:26693109:G:C	W78C	1.000
2:26693109:G:T	W78C	1.000
2:26693131:T:C	F86L	1.000
2:26693132:T:C	F86S	1.000
2:26693133:C:A	F86L	1.000
2:26693133:C:G	F86L	1.000
2:26693144:T:A	V90D	1.000
2:26693150:C:T	T92I	1.000
2:26693158:G:C	G95R	1.000
2:26727667:G:A	G95D	1.000
2:26727667:G:T	G95V	1.000
2:26727669:T:C	Y96H	1.000
2:26727672:G:T	G97W	1.000
2:26727673:G:A	G97E	1.000
2:26727673:G:T	G97V	1.000
2:26727685:C:A	P101H	1.000
2:26727712:G:A	C110Y	1.000
2:26727713:C:G	C110W	1.000
2:26727732:G:C	G117R	1.000
2:26727733:G:A	G117D	1.000
2:26727733:G:T	G117V	1.000
2:26727739:C:A	P119Q	1.000
2:26727748:T:A	L122H	1.000
2:26727904:G:A	G174D	1.000
2:26727915:T:C	F178L	1.000

dbSNP variants (sampled 300 via entrez): RS1000073882 (2:26709587 C>T), RS1000096411 (2:26731987 T>C,G), RS1000287078 (2:26708171 T>C), RS1000459101 (2:26698282 T>C), RS1000461812 (2:26702192 T>A), RS1000643296 (2:26691920 A>G), RS1000659605 (2:26732547 C>T), RS1000677862 (2:26700904 C>T), RS1000721271 (2:26719989 A>C), RS1000773070 (2:26726213 C>T), RS1000815165 (2:26700758 C>G), RS1000844694 (2:26714167 A>T), RS1000874152 (2:26713990 C>G,T), RS1001005763 (2:26708610 C>A,T), RS1001041429 (2:26706828 C>T)

Disease associations

OMIM: gene MIM:603220 | disease phenotypes: MIM:615344, MIM:621402, MIM:178600

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary arterial hypertension	Definitive	Autosomal dominant
pulmonary hypertension, primary, 4	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant
heritable pulmonary arterial hypertension	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pulmonary arterial hypertension	Definitive	AD

Mondo (7): pulmonary hypertension, primary, 4 (MONDO:0014136), pulmonary arterial hypertension (MONDO:0015924), autism spectrum disorder (MONDO:0005258), developmental delay with sleep apnea (MONDO:0980728), pulmonary hypertension, primary, 1 (MONDO:0024533), heritable pulmonary arterial hypertension (MONDO:0017148), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), Pulmonary arterial hypertension (Orphanet:182090), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000062	Ambiguous genitalia
HP:0000154	Wide mouth
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000463	Anteverted nares
HP:0000473	Torticollis
HP:0000490	Deeply set eye
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001059	Pterygium
HP:0001060	Axillary pterygium
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001344	Absent speech
HP:0001371	Flexion contracture
HP:0001382	Joint hypermobility
HP:0001511	Intrauterine growth retardation
HP:0001561	Polyhydramnios
HP:0001776	Bilateral talipes equinovarus
HP:0001838	Rocker bottom foot
HP:0001883	Talipes
HP:0001884	Talipes calcaneovalgus

GWAS associations

80 associations (top):

Study	Trait	p-value
GCST002783_438	Body mass index	1.000000e-09
GCST002783_513	Body mass index	1.000000e-09
GCST002783_86	Body mass index	1.000000e-08
GCST003275_4	Mean arterial pressure	5.000000e-21
GCST004775_16	Pulse pressure	6.000000e-08
GCST004776_11	Systolic blood pressure	2.000000e-15
GCST004777_30	Diastolic blood pressure	3.000000e-13
GCST004904_146	Body mass index	1.000000e-13
GCST005803_9	Corneal astigmatism	6.000000e-06
GCST005830_69	Hand grip strength	4.000000e-09
GCST005978_6	Diastolic blood pressure	6.000000e-13
GCST005979_7	Systolic blood pressure	1.000000e-21
GCST006009_13	Pulse pressure	4.000000e-11
GCST006010_3	Mean arterial pressure	8.000000e-19
GCST006031_3	Potassium levels	1.000000e-08
GCST006166_109	Diastolic blood pressure x alcohol consumption interaction (2df test)	3.000000e-32
GCST006166_49	Diastolic blood pressure x alcohol consumption interaction (2df test)	1.000000e-23
GCST006167_36	Mean arterial pressure x alcohol consumption interaction (2df test)	4.000000e-300
GCST006167_72	Mean arterial pressure x alcohol consumption interaction (2df test)	8.000000e-30
GCST006168_15	Pulse pressure x alcohol consumption interaction (2df test)	3.000000e-14
GCST006169_22	Diastolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	5.000000e-11
GCST006170_43	Systolic blood pressure x alcohol consumption (light vs heavy) interaction (2df test)	1.000000e-13
GCST006172_7	Mean arterial pressure x alcohol consumption (light vs heavy) interaction (2df test)	6.000000e-14
GCST006187_6	Diastolic blood pressure (cigarette smoking interaction)	1.000000e-51
GCST006188_20	Systolic blood pressure (cigarette smoking interaction)	5.000000e-61
GCST006258_45	Diastolic blood pressure	2.000000e-12
GCST006259_29	Systolic blood pressure	6.000000e-12
GCST006434_75	Systolic blood pressure x alcohol consumption interaction (2df test)	3.000000e-34
GCST006479_73	Diverticular disease	8.000000e-07
GCST006697_2	Parental longevity (combined parental attained age, Martingale residuals)	5.000000e-06

EFO canonical traits (26, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0006340	mean arterial pressure
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:1002040	Corneal astigmatism
EFO:0006941	grip strength measurement
EFO:0009283	potassium measurement
EFO:0004329	alcohol drinking
EFO:0006527	smoking status measurement
EFO:0009959	diverticular disease
EFO:0007796	parental longevity
EFO:0009927	Antihypertensive use measurement
EFO:0009929	Beta blocking agent use measurement
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0009762	healthspan
EFO:0009749	age at first sexual intercourse measurement
EFO:0004348	hematocrit
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2321613 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 94,967 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1077896	ROPIVACAINE	4	17,078
CHEMBL1098	BUPIVACAINE	4	37,899
CHEMBL492	ETIDOCAINE	4	11,778
CHEMBL558	MEXILETINE	4	15,463
CHEMBL631	PROPAFENONE	4	12,711
CHEMBL5095055	BAFREKALANT	2	38

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1275988	Efficacy	3	candesartan	Hypertension
rs1275988	Other	3	sevoflurane

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1275988	KCNK3	3	3.00	2	candesartan;sevoflurane

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Two-pore domain potassium channels (K_2P)

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
AVE1231	Channel blocker	6.7	pIC50
R-(+)-methanandamide	Channel blocker	6.15	pIC50
KU124	Inhibition	5.85	pIC50
anandamide	Inhibition	5.6	pIC50
isoflurane	Positive	2.7	pEC50
arachidonic acid	Channel blocker	1.0	pIC50
Ba2+	Channel blocker	0.3	pIC50

Binding affinities (BindingDB)

515 measured of 537 human assays (537 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-N-(dicyclopropylmethyl)-8-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	13 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-N-[(1S)-1-phenylpropyl]-1-N-[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	13 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-((S)-2-Methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propyl]-amide	IC50	13 nM	US-9884860: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-(3-chloro-4-fluorophenyl)propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	15 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-[1-[(2,4-difluorophenyl)methyl]-5-(2-methylpropanoyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]benzonitrile	IC50	19 nM	US-9127001: Substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines, their use as medicament, and pharmaceutical preparations comprising them
6-[(2S)-2-methylpyrrolidine-1-carbonyl]-N-[(1R)-1-[5-(trifluoromethyl)thiophen-2-yl]propyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	21 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-[(2S)-2-ethylpyrrolidine-1-carbonyl]-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	25 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
5-N-[(1R)-1-(4-fluorophenyl)ethyl]-7-N-[(1R)-1-phenylpropyl]-2,3-dihydropyrrolo[2,1-b][1,3]thiazole-5,7-dicarboxamide	IC50	27 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
5-N-[(1R)-1-(4-fluorophenyl)ethyl]-7-N-[(1R)-1-phenylpropyl]-1,3-dihydropyrrolo[1,2-c][1,3]thiazole-5,7-dicarboxamide	IC50	33 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-N-(2-cyclopropylethyl)-8-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	36 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
5-[(2S)-2-methylpyrrolidine-1-carbonyl]-N-[(1R)-1-phenylpropyl]-2,3-dihydropyrrolo[2,1-b][1,3]thiazole-7-carboxamide	IC50	37 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-(2-chloro-5-fluorophenyl)propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	40 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-N-[(1R)-1-(6-methoxy-2-pyridinyl)propyl]-8-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	40 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-N-[(1R)-1-(5-methoxypyrazin-2-yl)propyl]-8-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	41 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-N-[(1R)-1-(4-fluorophenyl)ethyl]-8-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	42 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-N-[(1S)-1-cyclopropylethyl]-1-N-[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	42 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-(2,6-difluorophenyl)propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	44 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
8-N-[(1R)-1-(4-fluorophenyl)ethyl]-6-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	46 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
8-N-[(1R)-1-(4-fluorophenyl)ethyl]-1-methyl-6-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	46 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-[5-(cyclopropanecarbonyl)-1-[(2,4-difluorophenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]benzonitrile	IC50	47 nM	US-9127001: Substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines, their use as medicament, and pharmaceutical preparations comprising them
6-N-[(1R)-1-(4-fluorophenyl)ethyl]-8-N-[(1R)-1-(5-methoxypyrazin-2-yl)propyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	48 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-8-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	48 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-N-[(R)-cyclopropyl(phenyl)methyl]-1-N-[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	48 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-(2-chloro-4-fluorophenyl)propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	49 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-(2,4-difluorophenyl)propyl]-6-(pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	49 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-phenylpropyl]-6-[(2R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	49 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-[2,6-difluoro-4-(trifluoromethyl)phenyl]propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	50 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-N-[(1R)-1-(4-fluorophenyl)ethyl]-8-N-[(1R)-1-phenylethyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	50 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
1-N,3-N-bis[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	51 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-N-[(1R)-1-(4-fluorophenyl)ethyl]-8-N-[(1R)-1-[5-(trifluoromethyl)-2-pyridinyl]propyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	54 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
8-N-[(1R)-1-phenylpropyl]-6-N-[(1S)-1-pyrazin-2-ylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	57 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-N-[(1S)-1-(4-fluorophenyl)ethyl]-1-N-[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	58 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
US10414765, Example 4	IC50	59.9 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
ethyl 2-[(2R)-1-[6-[[(1R)-1-(4-fluorophenyl)ethyl]carbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carbonyl]pyrrolidin-2-yl]acetate	IC50	62 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-[5-(cyclobutanecarbonyl)-1-[(2,4-difluorophenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]benzonitrile	IC50	64 nM	US-9127001: Substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines, their use as medicament, and pharmaceutical preparations comprising them
N-[(1R)-1-(2-chlorophenyl)-2-methylpropyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	64 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-(2-chlorophenyl)propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	64 nM	US-9884860: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-[2-chloro-6-(trifluoromethyl)-3-pyridinyl]propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	65 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
8-N-[(1R)-1-pyrimidin-2-ylpropyl]-6-N-[(1R)-1-[4-(trifluoromethyl)phenyl]propyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	65 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
8-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-6-N-[(1S)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	67 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-[1-[(1R,2R)-4,6-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-propanoyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]benzonitrile	IC50	70 nM	US-9034897: Indanyl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridines, their use as medicament, and pharmaceutical preparations comprising them
6-N-[(1S)-1-(4-fluorophenyl)ethyl]-8-N-[(1R)-1-phenylpropyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	70 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-(3-chloro-4-methoxyphenyl)propyl]-6-[(2S)-2-methylpyrrolidine-1-carbonyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	73 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
N-[(1R)-1-phenylpropyl]-6-(pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	74 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-N-[(1R)-1-cyclopropylethyl]-1-N-[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	74 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-N-[(1R)-1-cyclopropylethyl]-3-N-methyl-1-N-[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	74 nM	US-9884860: Fused pyrroledicarboxamides and their use as pharmaceuticals
3-N-[(4-fluorophenyl)methyl]-3-N-methyl-1-N-[(1R)-1-phenylpropyl]-5,6,7,8-tetrahydroindolizine-1,3-dicarboxamide	IC50	75 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
6-[(2S)-2-methylpyrrolidine-1-carbonyl]-N-[(1R)-1-[6-(trifluoromethyl)-2-pyridinyl]propyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxamide	IC50	76 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals
US10414765, Example 48	IC50	78 nM	US-10414765: Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
8-N-[(1R)-1-(2-chlorophenyl)propyl]-6-N-(cyclopropylmethyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxamide	IC50	80 nM	US-9284333: Fused pyrroledicarboxamides and their use as pharmaceuticals

ChEMBL bioactivities

1320 potent at pChembl≥5 of 1364 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3182699
8.70	IC50	2	nM	CHEMBL3183497
8.70	IC50	2	nM	CHEMBL3182449
8.55	IC50	2.8	nM	CHEMBL5883778
8.52	IC50	3	nM	CHEMBL1086899
8.40	IC50	4	nM	CHEMBL1081188
8.40	IC50	4	nM	CHEMBL3188749
8.38	IC50	4.2	nM	CHEMBL5976530
8.37	IC50	4.3	nM	CHEMBL5953514
8.31	IC50	4.9	nM	CHEMBL5979320
8.30	IC50	5	nM	CHEMBL3182091
8.15	IC50	7	nM	CHEMBL148342
8.15	IC50	7	nM	CHEMBL3187764
8.12	IC50	7.54	nM	CHEMBL5895677
8.10	IC50	7.9	nM	CHEMBL6016320
8.05	IC50	9	nM	CHEMBL3187482
8.03	IC50	9.3	nM	CHEMBL5804714
8.01	IC50	9.7	nM	CHEMBL5189300
8.00	IC50	10	nM	CHEMBL3183773
8.00	IC50	10	nM	CHEMBL3182359
8.00	IC50	10	nM	CHEMBL3182449
7.96	IC50	11	nM	CHEMBL3186000
7.96	IC50	11	nM	CHEMBL3187482
7.94	IC50	11.4	nM	CHEMBL5925518
7.89	IC50	13	nM	CHEMBL3916254
7.89	IC50	13	nM	CHEMBL4108886
7.89	IC50	13	nM	CHEMBL4113638
7.89	IC50	13	nM	CHEMBL5845985
7.87	IC50	13.4	nM	CHEMBL5781241
7.85	IC50	14	nM	CHEMBL3188857
7.82	IC50	15	nM	CHEMBL3967700
7.80	IC50	16	nM	CHEMBL1081188
7.75	IC50	17.9	nM	CHEMBL5766027
7.75	IC50	17.6	nM	CHEMBL5925518
7.72	IC50	19	nM	CHEMBL3940405
7.72	IC50	19.2	nM	CHEMBL5900523
7.69	IC50	20.5	nM	CHEMBL6059181
7.69	IC50	20.6	nM	CHEMBL5885911
7.68	IC50	21	nM	CHEMBL3186489
7.68	IC50	21	nM	CHEMBL3893027
7.68	IC50	21	nM	BAFREKALANT
7.66	IC50	21.7	nM	CHEMBL5866632
7.64	IC50	23	nM	CHEMBL3186695
7.62	IC50	24	nM	CHEMBL5757092
7.60	IC50	25	nM	CHEMBL3182551
7.60	IC50	25	nM	CHEMBL3977606
7.57	IC50	27	nM	CHEMBL1310568
7.57	IC50	27	nM	CHEMBL4115400
7.54	IC50	29	nM	CHEMBL3182777
7.54	IC50	29	nM	CHEMBL3182725

PubChem BioAssay actives

85 with measured affinity, of 173 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-propan-2-yloxy-N-[3-[[2-(trifluoromethoxy)benzoyl]amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0010	uM
N-[3-[(2-ethoxybenzoyl)amino]phenyl]-2-methoxybenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0020	uM
N-[3-[(2-ethoxybenzoyl)amino]phenyl]-2-(trifluoromethyl)benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0020	uM
N-[3-[(3-chlorobenzoyl)amino]phenyl]-3-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0030	uM
2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0040	uM
2-methoxy-N-[3-[[2-(trifluoromethoxy)benzoyl]amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0040	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]thiophene-2-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0050	uM
N-[3-[(2-methoxybenzoyl)amino]phenyl]-2-propan-2-ylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0070	uM
N-[(2,4-difluorophenyl)methyl]-2-[2-[[[2-(4-methoxyphenyl)acetyl]amino]methyl]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0070	uM
2-ethoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0090	uM
2-methoxy-N-[3-[(2-methoxybenzoyl)amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0100	uM
3-methyl-N-[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0100	uM
2-propan-2-yl-N-[3-[[2-(trifluoromethoxy)benzoyl]amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0110	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]-2-(trifluoromethyl)benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0140	uM
N-(3-benzamidophenyl)benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0210	uM
2-chloro-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0230	uM
N-[3-[(3-fluorobenzoyl)amino]phenyl]-3-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0250	uM
N-(3-benzamidophenyl)-3-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0270	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]-2-(trifluoromethoxy)benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0290	uM
N-(3-benzamidophenyl)thiophene-2-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0290	uM
3-methyl-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0300	uM
N-[3-[(3-methoxybenzoyl)amino]phenyl]-3-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0310	uM
N-(3-benzamidophenyl)furan-2-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0370	uM
N-(3-benzamidophenyl)-3-fluorobenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0450	uM
N-(3-benzamidophenyl)-3-chlorobenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0520	uM
N-[3-[(2-methoxybenzoyl)amino]phenyl]-2-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0730	uM
N-[3-(cyclohexanecarbonylamino)phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0790	uM
N-(3-benzamidophenyl)pyridine-2-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0860	uM
2-methyl-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0910	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]pyridine-4-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.0950	uM
N-(3-benzamidophenyl)-2-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1000	uM
(5Z,8Z,11Z,14Z)-N-[(2R)-1-hydroxypropan-2-yl]icosa-5,8,11,14-tetraenamide	1525567: Inhibition of human TASK1 expressed in African green monkey COS cells by whole cell patch clamp assay	ic50	0.1000	uM
N-(3-benzamidophenyl)-2-(trifluoromethyl)benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1300	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]furan-2-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1400	uM
3-benzamido-N-(2-ethylphenyl)benzamide	1849489: Inhibition of human TASK-1 expressed in Xenopus laevis oocytes assessed as inhibition of channel current at +40mV holding potential by two-electrode voltage clamp assay	ic50	0.1480	uM
2,5-dimethoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1500	uM
N-[3-[(4-chlorobenzoyl)amino]phenyl]-3-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1500	uM
N-[3-[[4-(dimethylamino)benzoyl]amino]phenyl]-3-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1500	uM
N-(3-benzamidophenyl)-3-(trifluoromethyl)benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1600	uM
N-(3-benzamidophenyl)thiophene-3-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1600	uM
2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]pyridine-4-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1800	uM
N-[3-[(4-tert-butylbenzoyl)amino]phenyl]-3-methylbenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.1900	uM
N-[(1R)-1-(6-methoxy-3-pyridinyl)propyl]-2-(propylsulfonylamino)benzamide	1849489: Inhibition of human TASK-1 expressed in Xenopus laevis oocytes assessed as inhibition of channel current at +40mV holding potential by two-electrode voltage clamp assay	ic50	0.2000	uM
benzyl N-[[2-[2-(2-pyridin-2-ylethylcarbamoyl)phenyl]phenyl]methyl]carbamate	1525553: Inhibition of human TASK1 expressed in Xenopus oocytes by whole cell voltage clamp assay	ic50	0.2000	uM
N-[3-[(3-methylbenzoyl)amino]phenyl]-2-propan-2-yloxybenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.2100	uM
N-(3-benzamidophenyl)-2-methoxybenzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.2200	uM
2-(butylsulfonylamino)-N-[1-(6-methoxy-3-pyridinyl)propyl]benzamide	1525555: Inhibition of human TASK1 by whole cell voltage clamp assay	ic50	0.2200	uM
N-(3-benzamidophenyl)pyridine-4-carboxamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.2500	uM
N-(3-benzamidophenyl)-4-(dimethylamino)benzamide	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.2600	uM
1-[1-[6-(4-phenylbenzoyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-4-yl]piperidin-4-yl]butan-1-one	1183445: Inhibition of TASK-1 (unknown origin) expressed in CHO cells by thallium flux assay	ic50	0.3000	uM

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
2-(4-amylcinnamoyl)amino-4-chlorobenzoic acid	increases activity, decreases response to substance	1
sanshool	increases transport, decreases activity, affects response to substance, affects binding, decreases reaction	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, affects cotreatment	1
licochalcone B	decreases expression	1
riociguat	decreases response to substance, increases activity	1
Sunitinib	increases expression	1
Carvedilol	decreases activity	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	increases expression	1
Folic Acid	decreases expression	1
Potassium	decreases reaction, affects binding, increases transport	1
Progesterone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Sodium Hydroxide	increases activity, decreases response to substance	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Toluene	decreases methylation, increases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Paclitaxel	increases expression	1

ChEMBL screening assays

39 unique, capped per target: 38 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2327429	Binding	Inhibition of TASK-1 (unknown origin)	Ion channels as therapeutic targets: a drug discovery perspective. — J Med Chem
CHEMBL3215269	Functional	PubChem BioAssay. SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel TASK1 (KCNK3). (Class of assay: confirmatory)	PubChem BioAssay data set

Clinical trials (associated diseases)

302 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
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