KCNH2

Summary

KCNH2 (potassium voltage-gated channel subfamily H member 2, HGNC:6251) is a protein-coding gene on chromosome 7q36.1, encoding Voltage-gated inwardly rectifying potassium channel KCNH2 (Q12809). Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified.

Source: NCBI Gene 3757 — RefSeq curated summary.

At a glance

• Gene–disease (curated): long QT syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 59
• Clinical variants (ClinVar): 3,820 total — 494 pathogenic, 162 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 706 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000238

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6251
Approved symbol	KCNH2
Name	potassium voltage-gated channel subfamily H member 2
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	Kv11.1, HERG, erg1
Ensembl gene	ENSG00000055118
Ensembl biotype	protein_coding
OMIM	152427
Entrez	3757

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 retained_intron, 6 protein_coding

ENST00000262186, ENST00000330883, ENST00000461280, ENST00000473610, ENST00000532957, ENST00000683359, ENST00000684116, ENST00000684241, ENST00000713700, ENST00000713701, ENST00000713710, ENST00000945646, ENST00000945647

RefSeq mRNA: 7 — MANE Select: NM_000238 NM_000238, NM_001204798, NM_001406753, NM_001406755, NM_001406756, NM_172056, NM_172057

CCDS: CCDS5910, CCDS5911

Canonical transcript exons

ENST00000262186 — 15 exons

Exon	Start	End
ENSE00000872388	150944961	150945514
ENSE00000872389	150948444	150948543
ENSE00000978099	150948856	150949049
ENSE00001141370	150946877	150947054
ENSE00001141375	150947328	150947514
ENSE00001141381	150947606	150947878
ENSE00002511912	150950168	150950420
ENSE00003469830	150959572	150959736
ENSE00003526373	150952425	150952853
ENSE00003531790	150958059	150958502
ENSE00003562537	150951448	150951835
ENSE00003570568	150950921	150951120
ENSE00003634780	150957291	150957502
ENSE00003726746	150974711	150974941
ENSE00004020818	150977838	150978321

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 95.99.

FANTOM5 (CAGE): breadth broad, TPM avg 9.7590 / max 345.2428, expressed in 550 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86835	6.0367	229
86843	1.7547	439
86833	1.2722	149
86836	0.2575	61
86834	0.2110	59
86842	0.1892	95
86841	0.0377	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	95.99	gold quality
right atrium auricular region	UBERON:0006631	95.19	gold quality
cardiac atrium	UBERON:0002081	94.63	gold quality
heart left ventricle	UBERON:0002084	94.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.70	gold quality
cardiac ventricle	UBERON:0002082	93.66	gold quality
pituitary gland	UBERON:0000007	93.06	gold quality
cerebellar hemisphere	UBERON:0002245	93.00	gold quality
cerebellar cortex	UBERON:0002129	92.89	gold quality
left ventricle myocardium	UBERON:0006566	92.70	gold quality
adenohypophysis	UBERON:0002196	92.24	gold quality
cerebellum	UBERON:0002037	91.93	gold quality
right testis	UBERON:0004534	91.09	gold quality
left testis	UBERON:0004533	90.98	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.89	gold quality
endothelial cell	CL:0000115	89.20	silver quality
heart	UBERON:0000948	89.14	gold quality
myocardium	UBERON:0002349	89.01	gold quality
testis	UBERON:0000473	88.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.69	gold quality
lower esophagus	UBERON:0013473	88.66	gold quality
trabecular bone tissue	UBERON:0002483	88.46	gold quality
cortical plate	UBERON:0005343	88.14	gold quality
sigmoid colon	UBERON:0001159	87.97	gold quality
body of uterus	UBERON:0009853	86.87	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.78	gold quality
bone marrow	UBERON:0002371	85.74	gold quality
left uterine tube	UBERON:0001303	85.46	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	817.91
E-CURD-98	yes	496.67
E-ANND-5	yes	481.11
E-MTAB-7407	yes	416.00
E-MTAB-10432	yes	292.50
E-CURD-112	yes	250.06
E-MTAB-9067	yes	185.08
E-HCAD-6	yes	53.24
E-CURD-122	yes	23.48
E-GEOD-137537	yes	18.78
E-ANND-3	yes	8.63
E-MTAB-9801	yes	4.48
E-MTAB-5061	no	3.10
E-HCAD-10	no	1.91

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
NR4A1	Activation

Upstream regulators (CollecTRI, top): AR, HSPA1A, HSPA1B, NFKB, NKX3-1, RNF207, SP1

miRNA regulators (miRDB)

23 targeting KCNH2, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6870-5P	99.99	68.55	2115
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-6825-5P	99.96	69.81	3431
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-365A-3P	99.43	70.02	836
HSA-MIR-365B-3P	99.43	70.02	836
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-2278	97.30	66.19	1130
HSA-MIR-4749-3P	96.40	66.24	798
HSA-MIR-3918	96.13	64.65	1300

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. (PMID:11741928)
• Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations (PMID:11854117)
• Mapping the binding site of a human ether-a-go-go-related gene-specific peptide toxin (ErgTx) to the channel’s outer vestibule (PMID:11864985)
• a key function of the C-terminal 104 amino acids is to mask the RGR ER retention signal, which becomes exposed when mutations truncate the HERG C terminus. (PMID:12021266)
• The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females. (PMID:12142119)
• identification of the residues that are important for the binding specificity to the scorpion toxin BeKm-1 (PMID:12151390)
• positioning of S6 aromatic residues relative to the central cavity of the channel, not inactivation per se determines drug block of HERG or eag channels (PMID:12209010)
• the cytoplasmic C terminus of HERG participates in the tethering or possibly targeting of HERG-containing vesicles within the Golgi via its interaction with GM130 (PMID:12270925)
• determination of relation of a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation (PMID:12354768)
• Description of a HERG isoform found in human and rabbit colon that has a functional role in smooth muscle (PMID:12427763)
• cell cycle dependent expression of isoforms in tumor cells (PMID:12431979)
• Three KCNH2 mutations, L413P, E444D and L559H were identified in long QT syndrome in China. (PMID:12442276)
• We conclude that normal HERG function in HEK293 cells requires basal activity of PKB. Our data represent the first evidence that PKB phosphorylation regulates K(+) channels (PMID:12527373)
• Different proximal amino-terminal domain sequences contribute to set HERG gating characteristics and its regulation by TRH (PMID:12560090)
• sustains a cardiac-type action potential in neuroblastoma S cells (PMID:12593854)
• The strong effects of Cs+ on inactivation but not on activation highlight the importance of ion and channel interactions during the onset of inactivation in the HERG channel. (PMID:12626667)
• Transcripts for HERG1 were present in all adenomas and although transcripts for HERG2 and HERG3 were also detected, their expression level was more variable. (PMID:12634931)
• Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. (PMID:12695533)
• gene expression; KCNH2 channels play a fundamental role in the control of motility patterns in human jejunum through their ability to modulate the electrical behavior of smooth muscle cells (PMID:12736144)
• procainamide inhibits the HERG K(+) channel by a primarily ‘open’ or ‘activated’ channel state blocking mechanism and that avidity of drug-binding is decreased by extensive I(HERG) inactivation (PMID:12804575)
• defective trafficking as a common mechanism for abnormal channel function resulting from mutations of critical COOH-terminal residues, including the long QT syndrome mutant HERGN861I (PMID:12885765)
• the amphipathic helix in the S5P linker interacts with the pore region of the channel in a voltage-dependent manner (PMID:12902341)
• erythromycin and clarithromycin significantly inhibit the HERG potassium current at clinically relevant concentrations (PMID:14674677)
• In 2 of 3 families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death,we identified 2 different missense mutations in the cardiac IKr channel HERG (KCNH2). (PMID:14676148)
• HERG C-terminus mutations may have a role in with long QT syndrome (PMID:14714110)
• herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers (PMID:14744775)
• that the TNF-alpha/TNFR1 system impairs HERG/I(Kr) function mainly by stimulating reactive oxygen species, particularly superoxide anion, but not by altering HERG expression (PMID:14973143)
• Four single nucleotide polymorphisms were identified in sudden infant death syndrome: K897T, P967L, R1047L, and Q1068R. (PMID:14975928)
• The KCNH2 A561T mutant channel revealed a post-translational defect that resulted in absence of the voltage-dependent delayed rectifier potassium current. (PMID:15120823)
• WT channels K525 stabilizes the closed state, R531 stabilizes the open state and R534 participates in interactions that stabilize pre-open closed states. (PMID:15181157)
• HERG channels are selectively involved in proliferation of distinct uterine cancer cells. (PMID:15202000)
• The NMR structure of gamma-KTx1.1 & critical residues for its binding to hERG channel were studied, showing a novel interaction between scorpion gamma-KTx & hERG channel, in which the toxin acts as a turret blocker over the channel’s outer vestibule. (PMID:15211519)
• Physiological role for PIP2 regulation of the rapidly activating delayed rectifier K+ current during autonomic stimulation and localize a site of interaction to the COOH-terminal tail of the HERG K+ channel. (PMID:15231497)
• native ventricular IKr channels are heteromers containing two alpha subunit types, ERG1a and -1b (PMID:15304481)
• T1945+6C is a disease-causing mutation. It alters KCNH2 splicing and cosegregates with the LQT2 phenotype. (PMID:15364333)
• Here we describe the mechanism by which both drugs block human Eag1 (hEag1) channels. (PMID:15365094)
• currents are modulated by alpha(1A)-adrenoceptors via protein kinases A and C (PMID:15365637)
• analysis of HERG channel function by dynamic action potential clamp technique (PMID:15475579)
• 1047L in leads KCNH2 to a functional impairment of the KCNH2 channel, which may contribute to the higher incidence of Torsades de Pointes in 1047L carriers when challenged with a channel blocker. (PMID:15522280)
• results define regions on the S4 domain voltage sensor that contribute differentially to hERG activation and inactivation gating (PMID:15528201)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	kcnh2a	ENSDARG00000029881
danio_rerio	KCNH2	ENSDARG00000106473
mus_musculus	Kcnh2	ENSMUSG00000038319
rattus_norvegicus	Kcnh2	ENSRNOG00000009872
drosophila_melanogaster	sei	FBGN0003353
drosophila_melanogaster	Elk	FBGN0011589
drosophila_melanogaster	CG6026	FBGN0038676
drosophila_melanogaster	CngA	FBGN0261612
drosophila_melanogaster	Cngl	FBGN0263257
drosophila_melanogaster	CngB	FBGN0266346
caenorhabditis_elegans		WBGENE00000487
caenorhabditis_elegans	tax-2	WBGENE00006525
caenorhabditis_elegans		WBGENE00006526
caenorhabditis_elegans		WBGENE00006830
caenorhabditis_elegans		WBGENE00022295

Paralogs (17): CNGB1 (ENSG00000070729), KCNH4 (ENSG00000089558), HCN2 (ENSG00000099822), CNGA4 (ENSG00000132259), KCNH3 (ENSG00000135519), HCN4 (ENSG00000138622), KCNH5 (ENSG00000140015), KCNH1 (ENSG00000143473), HCN3 (ENSG00000143630), CNGA3 (ENSG00000144191), HCN1 (ENSG00000164588), CNGB3 (ENSG00000170289), KCNH6 (ENSG00000173826), CNGA2 (ENSG00000183862), KCNH8 (ENSG00000183960), KCNH7 (ENSG00000184611), CNGA1 (ENSG00000198515)

Protein

Protein identifiers

Voltage-gated inwardly rectifying potassium channel KCNH2 — Q12809 (reviewed: Q12809)

Alternative names: Eag homolog, Ether-a-go-go-related gene potassium channel 1, Potassium voltage-gated channel subfamily H member 2, Voltage-gated potassium channel subunit Kv11.1

All UniProt accessions (5): A0A090N7X5, A0A090N8Q0, A0AAQ5BGQ9, A0AAQ5BGR0, Q12809

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Characterized by unusual gating kinetics by producing relatively small outward currents during membrane depolarization and large inward currents during subsequent repolarization which reflect a rapid inactivation during depolarization and quick recovery from inactivation but slow deactivation (closing) during repolarization. Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity. Has no inward rectifier potassium channel activity by itself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation. Has no inward rectifier potassium channel activity by itself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.

Subunit / interactions. The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits. Interacts with DNAJB12 and DNAJB14; chaperones DNAJB12 and DNAJB14 promote tetramerization. Heteromultimer with KCNH6/ERG2 and KCNH7/ERG3. Interacts with ALG10B. Forms a stable complex with KCNE1 or KCNE2, and that this heteromultimerization regulates inward rectifier potassium channel activity. Interacts with CANX. The core-glycosylated, but not the fully glycosylated form interacts with RNF207. Interacts with NDFIP1 and NDFIP2; this interaction decreases the cell membrane expression by targeting KCNH2, through interaction with NEDD4L, for the degradation through the multivesicular bodies (MVBs)-lysosomal pathway.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in heart and brain. Isoforms USO are frequently overexpressed in cancer cells.

Post-translational modifications. Phosphorylated on serine and threonine residues. Phosphorylation by PKA inhibits ion conduction.

Disease relevance. Long QT syndrome 2 (LQT2) [MIM:613688] A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. Deafness is often associated with long QT syndrome type 2. The disease is caused by variants affecting the gene represented in this entry. Short QT syndrome 1 (SQT1) [MIM:609620] A form of short QT syndrome, a heart disorder characterized by idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. It can cause syncope and sudden death. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The S4-S5 linker acts as a signal integrator where it both couples voltage-sensor domain (VSD) movement to pore opening and closure, as well as providing a binding site for other domains that regulate activation and/or deactivation of the channel.

Induction. Up-regulated by RNF207 (at protein level).

Miscellaneous. Twice more abundant than isoform 1 in heart. Primate-specific. Lacks a domain that is crucial for slow channel deactivation.

Similarity. Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.1/KCNH2 sub-subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q12809-1	A, KCNH2-1A	yes
Q12809-2	B, HERG1B
Q12809-4	4
Q12809-5	A-USO, HERG1USO
Q12809-6	B-USO, HERG1BUSO
Q12809-7	3.1, KCNH2-3.1

RefSeq proteins (3): NP_000229, NP_001393682, NP_742054 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR000595	cNMP-bd_dom	Domain
IPR000700	PAS-assoc_C	Domain
IPR001610	PAC	Repeat
IPR003938	K_chnl_volt-dep_EAG/ELK/ERG	Family
IPR003967	K_chnl_volt-dep_ERG	Family
IPR005821	Ion_trans_dom	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR050818	KCNH_animal-type	Family

Pfam: PF00027, PF00520, PF13426

Catalyzed reactions (Rhea), 1 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)

UniProt features (378 total): sequence variant 269, helix 26, strand 19, mutagenesis site 14, modified residue 10, topological domain 8, splice variant 7, transmembrane region 6, region of interest 5, compositionally biased region 4, turn 3, domain 2, chain 1, intramembrane region 1, coiled-coil region 1, short sequence motif 1, glycosylation site 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
6SYG	X-RAY DIFFRACTION	1.5
4HQA	X-RAY DIFFRACTION	1.96
4HP9	X-RAY DIFFRACTION	2.12
1BYW	X-RAY DIFFRACTION	2.6
9CHQ	ELECTRON MICROSCOPY	3
8ZYQ	ELECTRON MICROSCOPY	3.18
8ZYP	ELECTRON MICROSCOPY	3.19
8ZYN	ELECTRON MICROSCOPY	3.27
8ZYO	ELECTRON MICROSCOPY	3.29
9CHP	ELECTRON MICROSCOPY	3.3
9CHS	ELECTRON MICROSCOPY	3.4
8IO4	ELECTRON MICROSCOPY	3.5
9CHR	ELECTRON MICROSCOPY	3.5
5VA1	ELECTRON MICROSCOPY	3.7
5VA2	ELECTRON MICROSCOPY	3.8
8IO5	ELECTRON MICROSCOPY	3.8
8IOB	ELECTRON MICROSCOPY	3.9
5VA3	ELECTRON MICROSCOPY	4
1UJL	SOLUTION NMR
2L0W	SOLUTION NMR
2L1M	SOLUTION NMR
2L4R	SOLUTION NMR
2LE7	SOLUTION NMR
2N7G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12809-F1	63.94	0.29

Functional residue map

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

Post-translational modifications (10): 239, 243, 283, 284, 320, 351, 871, 874, 1014, 1137

Glycosylation sites (1): 598

Mutagenesis-validated functional residues (14):

Position	Phenotype
29	slows down deactivation.
43	slows down deactivation.
283	abolishes phosphorylation; when associated with a-890; a-895 and a-1137.
540	does not affect steady-state activation. significantly slow the activation rate at the most depolarised potentials. acce
543	increases the activation rate more rapidly at high voltages.
546	slows the activation rate.
548	perturbs steady-state activation. accelerates the activation rate at the most depolarised potentials. affects modestly t
550	slows the activation rate at low voltage gradients. increases the activation rate more rapidly at high voltages.
598	no effect on cell surface expression, but changes inactivation kinetics; when associated with a-631.
629	abolishes cell surface expression; has no effect on n-glycosylation.
631	no effect on cell surface expression, but changes inactivation kinetics; when associated with q-598.
890	abolishes phosphorylation; when associated with a-283; a-895 and a-1137.
895	abolishes phosphorylation; when associated with a-283; a-890 and a-1137.
1137	abolishes phosphorylation; when associated with a-283; a-890 and a-895.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1296072	Voltage gated Potassium channels
R-HSA-5576890	Phase 3 - rapid repolarisation
R-HSA-112316	Neuronal System
R-HSA-1296071	Potassium Channels
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 375 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GGGACCA_MIR133A_MIR133B, RNGTGGGC_UNKNOWN, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, TAATAAT_MIR126, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_VOLTAGE_GATED_POTASSIUM_CHANNELS, REACTOME_POTASSIUM_CHANNELS, PEREZ_TP63_TARGETS, GCANCTGNY_MYOD_Q6, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, MODULE_64, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOCC_CELL_SURFACE

GO Biological Process (27): regulation of heart rate by hormone (GO:0003064), potassium ion transport (GO:0006813), regulation of membrane potential (GO:0042391), positive regulation of DNA-templated transcription (GO:0045893), potassium ion homeostasis (GO:0055075), cardiac muscle contraction (GO:0060048), regulation of membrane repolarization (GO:0060306), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), cellular response to xenobiotic stimulus (GO:0071466), potassium ion transmembrane transport (GO:0071805), ventricular cardiac muscle cell action potential (GO:0086005), membrane repolarization (GO:0086009), membrane depolarization during action potential (GO:0086010), membrane repolarization during action potential (GO:0086011), membrane repolarization during cardiac muscle cell action potential (GO:0086013), regulation of heart rate by cardiac conduction (GO:0086091), potassium ion export across plasma membrane (GO:0097623), membrane repolarization during ventricular cardiac muscle cell action potential (GO:0098915), regulation of potassium ion transmembrane transport (GO:1901379), negative regulation of potassium ion transmembrane transport (GO:1901380), positive regulation of potassium ion transmembrane transport (GO:1901381), negative regulation of potassium ion export across plasma membrane (GO:1903765), potassium ion import across plasma membrane (GO:1990573), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (12): transcription cis-regulatory region binding (GO:0000976), inward rectifier potassium channel activity (GO:0005242), voltage-gated potassium channel activity (GO:0005249), delayed rectifier potassium channel activity (GO:0005251), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), scaffold protein binding (GO:0097110), voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization (GO:1902282), monoatomic ion channel activity (GO:0005216), potassium channel activity (GO:0005267), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), voltage-gated potassium channel complex (GO:0008076), cell surface (GO:0009986), perinuclear region of cytoplasm (GO:0048471), inward rectifier potassium channel complex (GO:1902937), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Potassium Channels	1
Cardiac conduction	1
Neuronal System	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
potassium ion transmembrane transport	3
cellular anatomical structure	3
regulation of membrane potential	2
membrane repolarization	2
ventricular cardiac muscle cell membrane repolarization	2
action potential	2
voltage-gated potassium channel activity	2
protein binding	2
regulation of heart rate by chemical signal	1
metal ion transport	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
striated muscle contraction	1
heart contraction	1
regulation of biological process	1
regulation of cardiac muscle cell membrane repolarization	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
potassium ion transport	1
monoatomic cation transmembrane transport	1
cardiac muscle cell action potential involved in contraction	1
membrane depolarization	1
cardiac muscle cell action potential	1
membrane repolarization during action potential	1
cardiac muscle cell membrane repolarization	1
regulation of heart rate	1
cardiac conduction	1
export across plasma membrane	1
ventricular cardiac muscle cell action potential	1
membrane repolarization during cardiac muscle cell action potential	1
regulation of potassium ion transport	1
regulation of monoatomic cation transmembrane transport	1
negative regulation of potassium ion transport	1
regulation of potassium ion transmembrane transport	1
negative regulation of cation transmembrane transport	1

Protein interactions and networks

STRING

1842 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KCNH2	KCNE2	Q9Y6J6	997
KCNH2	KCNE1	P15382	985
KCNH2	KCNQ1	P51787	984
KCNH2	SCN5A	Q14524	978
KCNH2	KCNJ2	P48049	931
KCNH2	KCNE3	Q9Y6H6	906
KCNH2	CACNA1C	Q13936	885
KCNH2	KCNA5	P22460	862
KCNH2	HSP90AA1	P07900	851
KCNH2	FLT1	P16057	849
KCNH2	SCN4B	Q8IWT1	827
KCNH2	HSP90AB1	P08238	819
KCNH2	A0A1W2PPA2	A0A1W2PPA2	813
KCNH2	KCNA2	P16389	810
KCNH2	KCNA3	P22001	805

IntAct

21 interactions, top by confidence:

A	B	Type	Score
KCNH2	KCNH2	psi-mi:“MI:0407”(direct interaction)	0.680
CAV1	KCNH2	psi-mi:“MI:0915”(physical association)	0.440
PASK	KCNH2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
KCNH2	CAV1	psi-mi:“MI:0403”(colocalization)	0.440
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
MAP1LC3B		psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350
KCNH2	KLHDC10	psi-mi:“MI:0914”(association)	0.350
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350
KCNH2	CDC73	psi-mi:“MI:0915”(physical association)	0.000
KCNH2	NDUFS6	psi-mi:“MI:0915”(physical association)	0.000
ARHH	KCNH2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (69): KCNH2 (Affinity Capture-MS), KCNH2 (Affinity Capture-Western), STUB1 (Affinity Capture-Western), HSPA8 (Affinity Capture-Western), HSPA1A (Affinity Capture-Western), RNF139 (Affinity Capture-Western), KCNH2 (Affinity Capture-Western), TRIOBP (Two-hybrid), KCNH2 (Two-hybrid), KCNH2 (FRET), TRIOBP (FRET), KCNH2 (FRET), KCNH2 (Affinity Capture-Western), TRIOBP (Co-localization), KCNH2 (Affinity Capture-Western)

ESM2 similar proteins: A2AJ88, B3MRI9, B3NY03, B4H3U8, B4IL64, B4JLX2, B4L535, B4M709, B4N1W9, B4Q0P3, B5DKS8, D3ZEF4, O08703, O08962, O35219, O54853, P25848, P59111, P97414, Q02331, Q12809, Q14999, Q17QV9, Q21534, Q3TRM4, Q5BK26, Q5R667, Q5RCJ3, Q5RDS0, Q5TEA3, Q67E00, Q67E01, Q6CF18, Q6ZV29, Q7TNL3, Q7TT23, Q8IY17, Q8N2I9, Q8RY24, Q8VE73

Diamond homologs: A5K0N4, G5EFJ9, O08703, O08962, O18965, O35219, O54852, O54853, O89047, O95259, P29281, P59111, Q02280, Q12809, Q60603, Q63472, Q8I719, Q8NCM2, Q8WNY2, Q920E3, Q96L42, Q9EPI9, Q9ER47, Q9H252, Q9NS40, Q9PT84, Q9QWS8, Q9R1T9, Q9TSZ3, Q9TUI4, Q9ULD8, Q9UQ05, Q9WVJ0, W7JX98, A0A509AKL0, O64511, P93025, Q1M667, Q2NCA3, Q2QYY8

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
cisapride	“down-regulates activity”	KCNH2	“chemical inhibition”
Terfenadine	“down-regulates activity”	KCNH2	“chemical inhibition”
NEDD4	“down-regulates quantity by destabilization”	KCNH2	ubiquitination
PRKD1	“down-regulates activity”	KCNH2	phosphorylation
KCNH2	“up-regulates activity”	ITGB1	binding
ITGB1	“up-regulates activity”	KCNH2	binding
NEDD4L	“down-regulates quantity by destabilization”	KCNH2	ubiquitination
MINK1	up-regulates	KCNH2	binding
PRKACA	up-regulates	KCNH2	phosphorylation
PTPN6	down-regulates	KCNH2	dephosphorylation
3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol	“down-regulates activity”	KCNH2	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

3820 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	494
Likely pathogenic	162
Uncertain significance	1519
Likely benign	1029
Benign	69

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1001814	NM_000238.4(KCNH2):c.1897A>C (p.Asn633His)	Pathogenic
1058879	NM_000238.4(KCNH2):c.1825_1830del (p.Asp609_Lys610del)	Pathogenic
1064605	NM_000238.4(KCNH2):c.2399-28del	Pathogenic
1068864	NC_000007.13:g.(?150644406)(150644976_?)del	Pathogenic
1068865	NC_000007.13:g.(?150642447)(150656830_?)del	Pathogenic
1068866	NC_000007.13:g.(?150654369)(150656834_?)del	Pathogenic
1068978	NM_000238.4(KCNH2):c.2555del (p.Phe852fs)	Pathogenic
1069284	NM_000238.4(KCNH2):c.1420_1472del (p.Thr474fs)	Pathogenic
1069329	NM_000238.4(KCNH2):c.544_556del (p.Ser182fs)	Pathogenic
1070517	NM_000238.4(KCNH2):c.669del (p.Leu225fs)	Pathogenic
1070541	NM_000238.4(KCNH2):c.3086_3099del (p.Ser1029fs)	Pathogenic
1070567	NM_000238.4(KCNH2):c.1707_1711dup (p.Ile571fs)	Pathogenic
1072040	NM_000238.4(KCNH2):c.3097_3106dup (p.Gly1036fs)	Pathogenic
1072580	NM_000238.4(KCNH2):c.2676_2680dup (p.Arg894fs)	Pathogenic
1072804	NM_000238.4(KCNH2):c.955_956del (p.Thr319fs)	Pathogenic
1073738	NM_000238.4(KCNH2):c.2931_2932insCTGGAGGCCCTTCTCCAGCCCCAGGCCCCCCGGAGAGCCGCCGGGTGGGGAGCCCCTGATGGAGGACTGC (p.Glu978fs)	Pathogenic
1074304	NM_000238.4(KCNH2):c.3101_3108del (p.Pro1034fs)	Pathogenic
1076264	NM_000238.4(KCNH2):c.3255dup (p.Pro1086fs)	Pathogenic
1076538	NM_000238.4(KCNH2):c.2682_2685dup (p.Asp896fs)	Pathogenic
1178326	NM_000238.4(KCNH2):c.1425C>A (p.Tyr475Ter)	Pathogenic
1191999	NM_000238.4(KCNH2):c.3032del (p.Glu1011fs)	Pathogenic
1201653	NM_000238.4(KCNH2):c.2108del (p.His703fs)	Pathogenic
1213540	NM_000238.4(KCNH2):c.1800del (p.Ser600fs)	Pathogenic
1219815	NM_000238.4(KCNH2):c.2774_2775delinsT (p.Gly925fs)	Pathogenic
1323136	NM_000238.4(KCNH2):c.774_789del (p.Asp259fs)	Pathogenic
1335697	NM_000238.4(KCNH2):c.41del (p.Phe14fs)	Pathogenic
1338861	NM_000238.4(KCNH2):c.418del (p.Ser140fs)	Pathogenic
1382290	NM_000238.4(KCNH2):c.307+1del	Pathogenic
1397577	NM_000238.4(KCNH2):c.1629dup (p.Glu544fs)	Pathogenic
1398420	NM_000238.4(KCNH2):c.2931_2941dup (p.Ser981fs)	Pathogenic

SpliceAI

3141 predictions. Top by Δscore:

Variant	Effect	Δscore
7:150946871:GCTTA:G	donor_loss	1.0000
7:150946872:CTTAC:C	donor_loss	1.0000
7:150946873:TTA:T	donor_loss	1.0000
7:150946874:TA:T	donor_loss	1.0000
7:150946875:A:AT	donor_loss	1.0000
7:150947051:CAGC:C	acceptor_gain	1.0000
7:150947323:CTCA:C	donor_loss	1.0000
7:150947324:TCAC:T	donor_loss	1.0000
7:150947325:CAC:C	donor_loss	1.0000
7:150947326:ACCT:A	donor_loss	1.0000
7:150948442:AC:A	donor_gain	1.0000
7:150948443:CC:C	donor_gain	1.0000
7:150948544:C:CC	acceptor_gain	1.0000
7:150948850:A:AC	donor_gain	1.0000
7:150948851:C:CC	donor_gain	1.0000
7:150948853:CA:C	donor_loss	1.0000
7:150948854:A:AC	donor_gain	1.0000
7:150948854:ACAT:A	donor_gain	1.0000
7:150948855:C:CC	donor_gain	1.0000
7:150948855:CA:C	donor_gain	1.0000
7:150948855:CAT:C	donor_gain	1.0000
7:150948855:CATC:C	donor_gain	1.0000
7:150948855:CATCT:C	donor_gain	1.0000
7:150949045:CTTCC:C	acceptor_gain	1.0000
7:150949046:TTCC:T	acceptor_gain	1.0000
7:150949047:TCCCT:T	acceptor_loss	1.0000
7:150949048:CCCTG:C	acceptor_loss	1.0000
7:150949050:C:CC	acceptor_gain	1.0000
7:150949050:CTGG:C	acceptor_loss	1.0000
7:150949051:T:A	acceptor_loss	1.0000

AlphaMissense

7508 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:150948893:A:G	F852S	1.000
7:150948904:G:C	F848L	1.000
7:150948904:G:T	F848L	1.000
7:150948905:A:G	F848S	1.000
7:150948906:A:G	F848L	1.000
7:150948959:A:G	L830P	1.000
7:150948959:A:T	L830Q	1.000
7:150948964:A:C	C828W	1.000
7:150948965:C:T	C828Y	1.000
7:150948974:A:G	L825P	1.000
7:150949031:C:T	G806E	1.000
7:150949032:C:A	G806W	1.000
7:150949032:C:G	G806R	1.000
7:150949032:C:T	G806R	1.000
7:150949033:A:C	F805L	1.000
7:150949033:A:T	F805L	1.000
7:150949034:A:G	F805S	1.000
7:150949035:A:G	F805L	1.000
7:150950170:A:G	L799P	1.000
7:150950173:A:T	I798N	1.000
7:150950177:C:G	A797P	1.000
7:150950206:A:T	I787N	1.000
7:150950212:C:A	G785V	1.000
7:150950212:C:T	G785D	1.000
7:150950213:C:G	G785R	1.000
7:150950224:A:G	F781S	1.000
7:150950260:A:G	L769P	1.000
7:150950293:A:G	F758S	1.000
7:150950302:G:T	A755D	1.000
7:150950303:C:G	A755P	1.000

dbSNP variants (sampled 300 via entrez): RS1000088604 (7:150961962 C>T), RS1000176105 (7:150957863 G>A), RS1000191523 (7:150964504 A>G), RS1000215372 (7:150978998 C>T), RS1000318092 (7:150964256 G>A), RS1000323501 (7:150967524 G>A), RS1000407935 (7:150972547 T>C), RS1000490069 (7:150970006 C>T), RS1000554815 (7:150974625 A>C,G), RS1000588177 (7:150952988 C>T), RS1000754776 (7:150970248 A>T), RS1000796084 (7:150974336 C>A,G), RS1001134650 (7:150947397 G>A), RS1001149610 (7:150945002 C>A,G), RS1001177525 (7:150948236 G>A)

Disease associations

OMIM: gene MIM:152427 | disease phenotypes: MIM:609620, MIM:613688, MIM:192500, MIM:601144, MIM:600996, MIM:604772, MIM:603829, MIM:617047, MIM:194200, MIM:616100, MIM:192600, MIM:115200, MIM:115080, MIM:113900

GenCC curated gene-disease

Disease	Classification	Inheritance
short QT syndrome type 1	Definitive	Autosomal dominant
long QT syndrome 2	Definitive	Autosomal dominant
Brugada syndrome	Moderate	Autosomal dominant
short QT syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
long QT syndrome	Definitive	AD
short QT syndrome	Definitive	AD
Brugada syndrome	Disputed	AD

Mondo (26): long QT syndrome (MONDO:0002442), cardiac rhythm disease (MONDO:0007263), short QT syndrome type 1 (MONDO:0012312), long QT syndrome 2 (MONDO:0013367), familial long QT syndrome (MONDO:0019171), obesity disorder (MONDO:0011122), long QT syndrome 1 (MONDO:0100316), Brugada syndrome (MONDO:0015263), short QT syndrome (MONDO:0000453), ventricular tachycardia (MONDO:0005477), catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376), Brugada syndrome 1 (MONDO:0011001), hypertrophic cardiomyopathy 26 (MONDO:0014883), torsades de pointes (MONDO:0005478)

Orphanet (18): Romano-Ward syndrome (Orphanet:101016), Congenital short QT syndrome (Orphanet:51083), Congenital long QT syndrome (Orphanet:768), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Brugada syndrome (Orphanet:130), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Idiopathic ventricular fibrillation (Orphanet:228140), Familial isolated restrictive cardiomyopathy (Orphanet:75249), Rare hypertrophic cardiomyopathy (Orphanet:217569), Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet:436159), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Familial dilated cardiomyopathy (Orphanet:217607), Dilated cardiomyopathy (Orphanet:217604), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Hereditary progressive cardiac conduction defect (Orphanet:871)

HPO phenotypes

27 total (30 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001657	Prolonged QT interval
HP:0001662	Bradycardia
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001678	Atrioventricular block
HP:0001688	Sinus bradycardia
HP:0001695	Cardiac arrest
HP:0001962	Palpitations
HP:0002900	Hypokalemia
HP:0003581	Adult onset
HP:0004308	Ventricular arrhythmia
HP:0004757	Paroxysmal atrial fibrillation
HP:0005110	Atrial fibrillation
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0011463	Childhood onset
HP:0012232	Shortened QT interval
HP:0012332	Abnormal autonomic nervous system physiology
HP:0025708	Early young adult onset
HP:0034303	Notched T wave
HP:0500018	Abnormal cardiac exercise stress test
HP:0001513	Obesity
HP:0001639	Hypertrophic cardiomyopathy
HP:0001716	Wolff-Parkinson-White syndrome

GWAS associations

59 associations (top):

Study	Trait	p-value
GCST000363_11	QT interval	5.000000e-16
GCST000363_12	QT interval	8.000000e-16
GCST000364_3	QT interval	2.000000e-15
GCST000561_16	Electrocardiographic traits	5.000000e-11
GCST000564_3	Electrocardiographic traits	3.000000e-06
GCST001746_4	QT interval	3.000000e-06
GCST002500_61	QT interval	1.000000e-49
GCST002500_62	QT interval	3.000000e-33
GCST003476_9	Eyebrow thickness	7.000000e-06
GCST005171_25	QT interval	4.000000e-13
GCST006061_181	Atrial fibrillation	7.000000e-10
GCST006061_182	Atrial fibrillation	9.000000e-11
GCST006414_127	Atrial fibrillation	2.000000e-11
GCST006479_100	Diverticular disease	2.000000e-06
GCST007218_13	QT interval	5.000000e-18
GCST007293_128	Body fat distribution (arm fat ratio)	5.000000e-10
GCST007293_58	Body fat distribution (arm fat ratio)	7.000000e-09
GCST007293_93	Body fat distribution (arm fat ratio)	3.000000e-15
GCST007576_134	Chronotype	5.000000e-08
GCST008129_19	Body mass index	5.000000e-15
GCST009016_5	T wave morphology restitution during exercise	2.000000e-11
GCST009068_5	T wave morphology restitution during exercise (MTAG)	1.000000e-11
GCST009602_59	Metabolic syndrome	2.000000e-09
GCST010346_17	TPE interval (resting)	4.000000e-23
GCST010346_34	TPE interval (resting)	1.000000e-13
GCST010346_50	TPE interval (resting)	2.000000e-08
GCST010796_1397	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-10
GCST010796_1398	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-12
GCST010796_1399	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-13
GCST010796_1400	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-14

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0004327	electrocardiography
EFO:0009959	diverticular disease
EFO:0004341	body fat distribution
EFO:0008328	chronotype measurement
EFO:0004340	body mass index
EFO:0008398	T wave morphology measurement
EFO:0000195	metabolic syndrome
EFO:0004644	TPE interval measurement

MeSH disease descriptors (16)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D016171	Torsades de Pointes	C14.280.067.845.940.700; C14.280.123.875.940.700; C23.550.073.845.940.700
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C563614	Long Qt Syndrome 2 (supp.)
C566506	Short QT Syndrome 1 (supp.)
C580439	Short Qt Syndrome (supp.)
C567851	Ventricular Fibrillation, Paroxysmal Familial, 1 (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2362996 (PROTEIN FAMILY), CHEMBL240 (SINGLE PROTEIN), CHEMBL4106188 (SELECTIVITY GROUP)

Molecules with ChEMBL bioactivity

706 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 369,997 (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
CHEMBL1000	CETIRIZINE	4	26,030
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL1023	BEXAROTENE	4	40,951
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1075	MORICIZINE	4	3,860
CHEMBL1078261	PROPIVERINE	4	4,890
CHEMBL1083659	SUVOREXANT	4	852
CHEMBL1085	ACETOPHENAZINE	4	5,134
CHEMBL1086	DIBUCAINE	4	17,231
CHEMBL1088	MESORIDAZINE	4	12,814
CHEMBL1094636	NIRAPARIB	4	6,433
CHEMBL1098	BUPIVACAINE	4	37,899
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1101	BIPERIDEN	4	11,044
CHEMBL1106	EPINASTINE	4	8,530
CHEMBL1107	HALOFANTRINE	4	9,722
CHEMBL1108	DROPERIDOL	4	16,888
CHEMBL111	RIMONABANT	4	15,726
CHEMBL1110	ALOSETRON	4	10,794
CHEMBL1112	ARIPIPRAZOLE	4	24,205
CHEMBL1113	AMOXAPINE	4
CHEMBL1117	IDARUBICIN	4
CHEMBL1123	DICYCLOMINE	4
CHEMBL1136	TELITHROMYCIN	4
CHEMBL1138	EZETIMIBE	4
CHEMBL114	SAQUINAVIR	4
CHEMBL1165342	VINCAMINE	4
CHEMBL1171837	PONATINIB	4
CHEMBL1172	DESLORATADINE	4
CHEMBL117287	PRUCALOPRIDE	4

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs104894021	Efficacy	3	disopyramide	short qt syndrome 1
rs104894021	Efficacy	3	quinidine	short qt syndrome 1
rs1137617	Efficacy	3	Calcium channel blockers;nitrendipine	Essential hypertension
rs12720441	Toxicity	3	amiodarone	Torsades de Pointes

PharmGKB variants

11 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1137617	KCNH2	3	2.25	1	Calcium channel blockers;nitrendipine
rs1805123	KCNH2		0.00	0
rs3807375	KCNH2		0.00	0
rs3815459	KCNH2		0.00	0
rs12720441	KCNH2	3	0.00	1	amiodarone
rs36210421	KCNH2		0.00	0
rs104894021	KCNH2	3	0.00	2	disopyramide;quinidine
rs199472959	KCNH2		0.00	0
rs199472944	KCNH2		0.00	0
rs138776684	KCNH2		0.00	0
rs3807372	KCNH2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Voltage-gated potassium channels (K_v)

Most potent curated ligand interactions (28 total), top 25:

Ligand	Action	Affinity	Parameter
astemizole	Channel blocker	9.0	pIC50
ErgTx-1	Channel blocker	8.3	pKd
BeKm-1	Channel blocker	8.2	pKd
dofetilide	Inhibition	8.19	pKi
E4031	Channel blocker	8.1	pIC50
ibutilide	Channel blocker	8.0	pIC50
γ-KTx1.7	Channel blocker	7.9	pKd
APETx-1	Inhibition	7.5	pIC50
halofantrine	Inhibition	7.4	pIC50
cisapride	Channel blocker	7.4	pIC50
terfenadine	Channel blocker	7.3	pIC50
rottlerin	Activation	6.5	pEC50
ginsenoside Rg3	Activation	6.4	pEC50
ICA-105574	Activation	6.3	pEC50
PF-04885614	Inhibition	5.74	pIC50
nemiralisib	Inhibition	5.5	pIC50
LUF7244	Negative	5.41	pIC50
danuglipron	Inhibition	5.03	pIC50
NS1643	Activation	5.0	pEC50
VU0405601	Activation	5.0	pEC50
KB-130015	Activation	4.9	pEC50
zorifertinib	Inhibition	4.88	pIC50
AZD3778	Inhibition	4.8	pIC50
MK-7145	Inhibition	4.66	pIC50
DA-302168S	Inhibition	4.52	pIC50

Binding affinities (BindingDB)

1070 measured of 1357 human assays (1528 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[(4R)-4-[3-(dimethylamino)propyl]-1-(2-fluoro-5-methylphenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-3-yl]ethan-1-one	IC50	0.2 nM
4,4-difluoro-N-[(1S)-3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-phenylpropyl]cyclohexane-1-carboxamide	KI	0.24 nM	US-9107954: Bivalent ligands for the treatment of neurological disorders
arylpyrazole, 31	EC50	0.31 nM
2,2-difluoro-3- ((1R,3R)-1-(5- fluoro-2-(2- ((3- fluoropropyl) amino)ethoxy)- 3- methylpyridin- 4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2- yl)propan-1-ol	IC50	0.43 nM	US-10221173: Chemical compounds
1-[[1-[3-(1,1-difluoroethyl)-4-fluorophenyl]triazol-4-yl]methyl]imidazol-2-amine	IC50	0.51 nM	US-9981950: Triazoles as NR2B receptor inhibitors
3-((1R,3R)-1- (6-fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2- yl)propanenitrile	IC50	0.54 nM	US-10221173: Chemical compounds
benzimidazole analogue, 7j	EC50	0.55 nM
3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol	IC50	0.55 nM	US-10221173: Chemical compounds
2,2-difluoro-3- ((1R,3R)-1-(2- (2-((3- fluoropropyl) amino)ethoxy)- 3- methylpyridin- 4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2- yl)propan-1-ol	IC50	0.56 nM	US-10221173: Chemical compounds
3-fluoro-N-(2- (3-((1R,3R)-2- ((1- fluorocyclopropyl) methyl)-3- methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 4- methoxyphenoxy) ethyl)propan- 1-amine	IC50	0.58 nM	US-10221173: Chemical compounds
benzimidazole analogue, 7p	EC50	0.59 nM
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine	KI	0.6 nM
3-((1R,3R)-1- (3-chloro-5- fluoro-2-(2- ((3- fluoropropyl) amino)ethoxy) pyridin-4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan- 1-ol	IC50	0.6 nM	US-10221173: Chemical compounds
Preparation of 3-fluoro-N-(2-((5-methoxy-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-2-yl)oxy)ethyl)propan-1-amine	IC50	0.62 nM	US-10221173: Chemical compounds
3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) amino)ethoxy) pyridin-4-yl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.64 nM	US-10221173: Chemical compounds
benzimidazole-based antagonist, 1	EC50	0.65 nM
N1-(2-fluoro- 4-methoxy-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenyl)-N2- (3- fluoropropyl) ethane-1,2- diamine	IC50	0.65 nM	US-10221173: Chemical compounds
5-((6S,8R)-1- fluoro-8- methyl-7- (2,2,2- trifluoroethyl)- 6,7,8,9- tetrahydro-3H- pyrazolo[4,3- f]isoquinolin- 6-yl)-N-(1-(3- fluoropropyl) azetidin-3- yl)pyrazin-2- amine	IC50	0.69 nM	US-10131663: Chemical compounds
3-((1R,3R)-1-(2,6-difluoro-3-(2-((3-fluoropropyl)amino)ethoxy)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol	IC50	0.69 nM	US-10221173: Chemical compounds
3-((1R,3R)-1- (2- (difluoromethyl)- 3-(2-((3- fluoropropyl) amino)ethoxy) phenyl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.69 nM	US-10221173: Chemical compounds
3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) (methyl)amino) ethoxy)pyridin- 4-yl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.7 nM	US-10221173: Chemical compounds
3-((1R,3R)-1- (2,6-difluoro- 3-(2-((3- fluoropropyl) amino)ethoxy) phenyl)-5- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.71 nM	US-10221173: Chemical compounds
3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) amino)ethoxy) pyridin-4-yl)- 3,6-dimethyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.71 nM	US-10221173: Chemical compounds
benzimidazole analogue, 7e	EC50	0.72 nM
3-((1R,3R)-1- (3-chloro-2-(2- ((3- fluoropropyl) amino)ethoxy) pyridin-4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan- 1-ol	IC50	0.72 nM	US-10221173: Chemical compounds
3-fluoro-N-(2- ((5-methyl-6- ((1S,3R)-3- methyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyrimidin- 4- yl)oxy)ethyl) propan-1-amine	IC50	0.74 nM	US-10221173: Chemical compounds
2,2-difluoro-3- ((1R,3R)-1-(6- fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 2- methylphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2- yl)propan-1-ol	IC50	0.78 nM	US-10221173: Chemical compounds
3-((1R,3R)-1- (2,6-difluoro- 3-(2-((3- fluoropropyl) amino)ethoxy) phenyl)-7- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.79 nM	US-10221173: Chemical compounds
2-Cyclohexylcarbonylbenzimidazole, 7e	IC50	0.8 nM
N-(2-(3- ((1R,3R)-2- (2,2- difluoroethyl)- 3-methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 2-fluoro-4- methoxyphenoxy) ethyl)-3- fluoropropan- 1-amine	IC50	0.8 nM	US-10221173: Chemical compounds
benzimidazole analogue, 7h	IC50	0.81 nM
1-(3-Fluoropropyl)-N-(4-((6R,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)phenyl)azetidin-3-amine	IC50	0.81 nM	US-10131663: Chemical compounds
3-((1R,3R)-1- (2,6-difluoro- 3-(2-((3- fluoropropyl) amino)ethoxy) phenyl)-8- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.84 nM	US-10221173: Chemical compounds
3-fluoro-N-(2- (4-methoxy-2- methyl-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)propan-1- amine	IC50	0.85 nM	US-10221173: Chemical compounds
2,2-difluoro-3- ((1R,3R)-6- fluoro-1-(2- fluoro-3-(2- ((3- fluoropropyl) amino)ethoxy)- 6- methoxyphenyl)- 3-methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2- yl)propan-1-ol	IC50	0.86 nM	US-10221173: Chemical compounds
2,2-difluoro-3- ((6S,8R)-1- fluoro-6-(5- ((1-(3- fluoropropyl) azetidin-3- yl)amino)pyridin- 2-yl)-8- methyl- 3,6,8,9- tetrahydro-7H- pyrazolo[4,3- f]isoquinolin- 7-yl)propan-1- ol	IC50	0.88 nM	US-10131663: Chemical compounds
N-(2-(2- chloro-3- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)phenoxy) ethyl)-3- fluoropropan- 1-amine	IC50	0.88 nM	US-10221173: Chemical compounds
2,2-difluoro-3-[(6S,8R)-1-fluoro-6-[5-[1-(3-fluoropropyl)azetidin-3-yl]oxy-2-pyridinyl]-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-7-yl]propan-1-ol	IC50	0.88 nM	US-10590130: Chemical compounds
benzimidazole analogue, 7m	EC50	0.9 nM
Preparation of 3-((1R,3R)-1-(5-fluoro-2-(2-((3-fluoropropyl)(methyl)amino)ethoxy)-3-methylpyridin-4-yl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butanoic acid	IC50	0.9 nM	US-10221173: Chemical compounds
benzimidazole analogue, 7o	EC50	0.91 nM
3-((1R,3R)-1- (2,6-difluoro- 3-((2-((3- fluoropropyl) amino)ethyl) amino)phenyl)-6- fluoro-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan- 1-ol	IC50	0.91 nM	US-10221173: Chemical compounds
3-fluoro-N-(2- ((3-methyl-4- ((1R,3R)-3- methyl-2- (2,2,2- trifluoroethyl)- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1- yl)pyridin-2- yl)oxy)ethyl) propan-1-amine	IC50	0.92 nM	US-10221173: Chemical compounds
2-fluoro-6- ((6S,8R)-1- fluoro-8- methyl-7- (2,2,2- trifluoroethyl)- 6,7,8,9- tetrahydro-3H- pyrazolo[4,3- f]isoquinolin- 6-yl)-N-(1-(3- fluoropropyl) azetidin-3- yl)pyridin-3- amine	IC50	0.94 nM	US-10131663: Chemical compounds
3-fluoro-N-(2- (2-fluoro-3- ((1R,3R)-2-((3- fluorooxetan- 3-yl)methyl)- 3-methyl- 2,3,4,9- tetrahydro-1H- pyrido[3,4- b]indol-1-yl)- 4- methoxyphenoxy) ethyl)propan- 1-amine	IC50	0.94 nM	US-10221173: Chemical compounds
3-((1R,3R)-1- (3,5-difluoro- 2-(2-((3- fluoropropyl) amino)ethoxy) pyridin-4-yl)-3- methyl- 1,3,4,9- tetrahydro-2H- pyrido[3,4- b]indol-2-yl)- 2,2- difluoropropan-1- ol	IC50	0.96 nM	US-10221173: Chemical compounds
N-[3-[(4aR,6S,8aS)-2-amino-6-methyl-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-8a-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide	IC50	1 nM	US-9744173: 2-amino 6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl-1,3-thiazol-4-yl amides
arylpyrazole, 28	EC50	1 nM
benzimidazole analogue, 7k	IC50	1 nM
2,2-difluoro-3- ((6S,8R)-1- fluoro-6-(6- fluoro-5-((1- (3- fluoropropyl) azetidin-3- yl)amino)pyridin- 2-yl)-8- methyl- 3,6,8,9- tetrahydro-7H- pyrazolo[4,3- f]isoquinolin- 7-yl)propan-1- ol	IC50	1 nM	US-10131663: Chemical compounds

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.68	IC50	0.021	nM	CHEMBL4595328
10.54	IC50	0.029	nM	CHEMBL327980
9.85	IC50	0.14	nM	CHEMBL5432371
9.85	IC50	0.14	nM	CHEMBL1257821
9.82	Ki	0.15	nM	CHEMBL5722941
9.74	IC50	0.18	nM	CHEMBL5722941
9.60	IC50	0.25	nM	CHEMBL1257820
9.59	IC50	0.26	nM	CHEMBL1257578
9.55	Ki	0.28	nM	CHEMBL3590463
9.42	IC50	0.38	nM	CHEMBL1257698
9.41	IC50	0.39	nM	CHEMBL3422978
9.41	Ki	0.39	nM	CHEMBL227134
9.40	Ki	0.4	nM	CHEMBL598270
9.39	IC50	0.41	nM	CHEMBL410832
9.37	IC50	0.43	nM	CHEMBL1257577
9.36	Kd	0.44	nM	CHEMBL3590463
9.32	IC50	0.48	nM	CHEMBL5858906
9.29	IC50	0.51	nM	CHEMBL5870278
9.29	IC50	0.51	nM	CHEMBL5794967
9.28	IC50	0.52	nM	CHEMBL6063759
9.28	IC50	0.52	nM	CHEMBL1257937
9.26	Ki	0.55	nM	CHEMBL1085090
9.25	Ki	0.56	nM	CHEMBL1085806
9.21	IC50	0.61	nM	CHEMBL1223951
9.21	IC50	0.62	nM	CHEMBL1257938
9.21	IC50	0.62	nM	CHEMBL1258280
9.19	IC50	0.65	nM	CHEMBL259732
9.19	IC50	0.65	nM	CHEMBL5956282
9.17	IC50	0.67	nM	CHEMBL1642479
9.16	IC50	0.69	nM	CHEMBL5944633
9.14	IC50	0.73	nM	CHEMBL3422952
9.14	Kd	0.73	nM	CHEMBL3590452
9.14	Ki	0.73	nM	CHEMBL1091775
9.14	IC50	0.72	nM	CHEMBL1258503
9.12	IC50	0.76	nM	CHEMBL2146867
9.09	IC50	0.81	nM	CHEMBL6009034
9.09	IC50	0.81	nM	CHEMBL1642487
9.06	IC50	0.87	nM	CHEMBL3422970
9.06	IC50	0.88	nM	CHEMBL5839811
9.05	IC50	0.89	nM	CHEMBL3422959
9.05	IC50	0.9	nM	ASTEMIZOLE
9.04	IC50	0.912	nM	ASTEMIZOLE
9.03	IC50	0.94	nM	CHEMBL4777139
9.02	IC50	0.95	nM	CHEMBL4171244
9.02	IC50	0.95	nM	CHEMBL1258725
9.00	IC50	1	nM	DESMETHEYLASTEMIZOLE
9.00	IC50	0.99	nM	CHEMBL3422977
9.00	IC50	1	nM	NAVACAPRANT
9.00	IC50	1	nM	CHEMBL5885156
8.96	IC50	1.1	nM	CHEMBL4457529

PubChem BioAssay actives

1985 with measured affinity, of 6100 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
N-[(4R,4aS,7S,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-1H-indole-7-carboxamide	1964636: Inhibition of human ERG expressed in CHO-K1 cells with holding potential of -80 mV by automated patch clamp assay	ic50	<0.0001	uM
2,6-diheptyl-1-methylpyridin-1-ium;trifluoromethanesulfonate	1234160: Displacement of [3H]dofetilide from human Kv11.1 expressed in HEK293 cell membranes by competitive radioligand displacement assay	ki	0.0003	uM
6-[[[1-[2-[7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0004	uM
6-[[[1-[2-[3-fluoro-7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0009	uM
2-methyl-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-3-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0009	uM
methyl 2-hydroxy-3-[N-[4-[(2S)-2-[(4-methylpiperazin-1-yl)methyl]-5-oxopyrrolidin-1-yl]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1504566: Inhibition of human ERG	ic50	0.0009	uM
6-[[[1-[2-[6-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0010	uM
1-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine	1624462: Inhibition of human ERG expressed in HEK293 cells at 10 uM by Qpatch clamp assay	ic50	0.0010	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-6,7-dichloro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0014	uM
6-[[[1-[2-(6,7-dimethoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0014	uM
methyl 2-hydroxy-3-[N-[4-[(2R)-2-[(4-methylpiperazin-1-yl)methyl]-5-oxopyrrolidin-1-yl]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1504566: Inhibition of human ERG	ic50	0.0014	uM
2-methoxy-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-3-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0016	uM
4-[(4-chlorophenyl)methoxy]-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyridin-2-one	551222: Displacement of [35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthyl]-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesulfonamide from human ERG expressed in HEK293 cells	ic50	0.0017	uM
6-[[[1-[2-[3-fluoro-6-methoxy-7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0017	uM
3-methoxy-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-2-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0020	uM
4-methyl-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-2-carbonitrile	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0021	uM
6-[[[1-[2-[6-(dimethylamino)-7-(trifluoromethyl)-1,5-naphthyridin-4-yl]ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0023	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-bromo-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0025	uM
6-[[[1-[2-(7-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0025	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1504566: Inhibition of human ERG	ic50	0.0026	uM
2-(3-ethylpyrazol-1-yl)-1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0029	uM
6-[[[1-[2-(7-chloro-3-fluoro-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0033	uM
1-methyl-2,6-di(nonyl)pyridin-1-ium;trifluoromethanesulfonate	1234160: Displacement of [3H]dofetilide from human Kv11.1 expressed in HEK293 cell membranes by competitive radioligand displacement assay	ki	0.0034	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-chloro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0036	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-(difluoromethoxy)-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0036	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-6-fluoro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0040	uM
6-[[[1-[2-(7-chloro-6-methoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0042	uM
6-[[[1-[2-(2,6-dimethoxy-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0042	uM
2-(1-bromonaphthalen-2-yl)oxy-N-pyridin-3-ylacetamide	1264994: Binding affinity to Kv11.1 channel (unknown origin)	ki	0.0048	uM
6-[[[1-[2-(7-chloro-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0049	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-cyano-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0050	uM
1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]-2-(3-methylpyrazol-1-yl)ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0050	uM
6-[[[1-[2-(6-methoxy-8-methyl-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0052	uM
7-fluoro-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0054	uM
N-[1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]piperidin-4-yl]-7-fluoro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0056	uM
1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]-2-(3-propan-2-yl-1,2,4-triazol-1-yl)ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0058	uM
1-[2-[4-[1-(4-fluorophenyl)indol-3-yl]piperidin-1-yl]ethyl]imidazolidine-2-thione	161283: Inhibition of K+ channel activity in CHO cells expressing HERG Kv11.1	ic50	0.0062	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-6,7-difluoro-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0062	uM
(4-chlorophenyl)-[9-[(2-phenoxyphenyl)methyl]-3,9-diazaspiro[5.5]undecan-3-yl]methanone	317758: Displacement of [3H]dofetilide from human recombinant ERG potassium channel expressed in HEK293 cells by patch clamp method	ic50	0.0065	uM
6-[[[1-[2-(8-methyl-6-methylsulfonyl-1,5-naphthyridin-4-yl)ethyl]-2-oxabicyclo[2.2.2]octan-4-yl]amino]methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0067	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0067	uM
1-[2-[4-[1-(4-fluorophenyl)indol-3-yl]piperidin-1-yl]ethyl]imidazolidin-2-one	576612: Inhibition of human ERG	ic50	0.0069	uM
1-[(2R)-2-methyl-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]-2-(3-propan-2-yl-1,2,4-triazol-1-yl)ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0070	uM
(3S,4S)-8-[7-(2,3-dichlorophenyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine	1614711: Inhibition of human ERG by Q-patch assay	ic50	0.0070	uM
2-(3-cyclopropyl-1,2,4-triazol-1-yl)-1-[(2R)-2-(2-hydroxyethyl)-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0073	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-7-ethyl-4-oxochromene-2-carboxamide	271871: Displacement of [3H]dofetilide from hERG	ic50	0.0074	uM
2-(3-tert-butyl-1,2,4-triazol-1-yl)-1-[(2R)-2-methyl-4-[2-(trifluoromethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-thiazol-5-yl]piperazin-1-yl]ethanone	1947871: Inhibition of human ERG stably expressed in CHO cells at -80 mV holding voltage by automated QPatch electrophysiological assay	ic50	0.0075	uM
ethyl 3-methoxy-8-[2-[4-[(3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)methylamino]-2-oxabicyclo[2.2.2]octan-1-yl]ethyl]-1,5-naphthyridine-4-carboxylate	1204043: Inhibition of MK499 binding to human ERG	ic50	0.0079	uM
(3R)-3-[[4-[[(E)-3-(2,5-difluorophenyl)prop-2-enyl]amino]-2-oxabicyclo[2.2.2]octan-1-yl]methyl]-5-fluoro-3-hydroxy-1,7-diazatricyclo[6.3.1.04,12]dodeca-4(12),5,7,9-tetraen-11-one	1204682: Displacement of MK499 from human ERG	ic50	0.0080	uM
4-phenylmethoxy-1-[4-(2-pyrrolidin-1-ylethoxy)phenyl]pyridin-2-one	551222: Displacement of [35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahydro-2-naphthyl]-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyran-2,40-piperidin]-6-yl]methanesulfonamide from human ERG expressed in HEK293 cells	ic50	0.0081	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Terfenadine	increases transport, decreases activity, affects binding, increases reaction, affects cotreatment (+1 more)	29
Astemizole	increases reaction, affects localization, affects binding, decreases activity, decreases reaction (+3 more)	20
Cisapride	increases transport, decreases activity, decreases reaction, affects localization, affects binding	19
E 4031	affects binding, increases activity, increases reaction, increases transport, decreases reaction (+4 more)	17
Quinidine	increases transport, decreases activity, decreases reaction, increases reaction, affects localization (+5 more)	16
dofetilide	affects binding, increases transport, increases reaction, affects reaction, affects cotreatment (+2 more)	15
Amiodarone	increases transport, increases reaction, affects activity, affects binding, decreases activity (+1 more)	14
Potassium	affects cotreatment, increases activity, decreases export, increases abundance, affects stability (+10 more)	11
Arsenic Trioxide	affects localization, decreases expression, decreases localization, increases degradation, increases expression (+6 more)	9
Fluoxetine	decreases reaction, increases transport, decreases expression, affects response to substance, affects localization (+2 more)	6
Ketoconazole	decreases activity, affects cotreatment, increases reaction, decreases response to substance, affects activity (+2 more)	6
Sotalol	decreases response to substance, decreases activity, decreases reaction, affects binding	6
Verapamil	decreases activity, decreases import, decreases reaction, increases transport	6
Loratadine	affects binding, decreases reaction, increases transport, affects cotreatment, decreases activity (+1 more)	6
Haloperidol	decreases reaction, increases transport, decreases activity	5
Propafenone	affects activity, affects binding, decreases activity, decreases reaction, increases transport	5
Tamoxifen	affects binding, decreases activity, decreases reaction, increases transport, decreases import	5
nefazodone	affects activity, affects binding, decreases activity	4
Domperidone	decreases reaction, increases transport, decreases activity, affects response to substance	4
Doxorubicin	decreases expression, affects reaction, decreases response to substance	4
Erythromycin	affects reaction, decreases response to substance, affects binding, decreases activity	4
Imipramine	affects binding, decreases activity, decreases reaction, increases transport	4
Pimozide	decreases reaction, increases transport, decreases activity	4
Thallium	increases transport, increases reaction, decreases activity, decreases import, increases import (+1 more)	4
Thioridazine	decreases reaction, increases transport, decreases activity	4
Bepridil	affects binding, decreases activity, decreases reaction, increases transport	4
sertindole	decreases reaction, increases transport, decreases activity	3
azimilide	decreases reaction, increases reaction, decreases activity	3
fexofenadine	decreases reaction, increases activity, decreases expression, increases degradation	3
Sunitinib	decreases activity	3

ChEMBL screening assays

4851 unique, capped per target: 3558 binding, 1071 toxicity, 169 functional, 53 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1787442	Binding	Inhibition of human recombinant Kv channel at 10 uM by radioligand binding assay	Structure-activity relationships of pyrrole based S-nitrosoglutathione reductase inhibitors: pyrrole regioisomers and propionic acid replacement. — Bioorg Med Chem Lett
CHEMBL5522525	Toxicity	Inhibition of human K+ channel by automated electrophysiology	Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure. — J Med Chem
CHEMBL1614368	ADMET	PUBCHEM_BIOASSAY: Dosage response for compounds that protect hERG from block by proarrhythmic agents using manual patch clamp. (Class of assay: confirmatory) [Related pubchem assays: 1680 (Summary assay for hERG assays.), 1511 (Primary HTS	PubChem BioAssay data set

Cellosaurus cell lines

49 cell lines: 34 induced pluripotent stem cell, 5 transformed cell line, 4 embryonic stem cell, 3 spontaneously immortalized cell line, 2 cancer cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1N94	GM25305	Induced pluripotent stem cell	Female
CVCL_9S61	UKKi009-A	Induced pluripotent stem cell	Female
CVCL_9S62	UKKi009-B	Induced pluripotent stem cell	Female
CVCL_A4JN	UMGi120-A.7	Induced pluripotent stem cell	Male
CVCL_A4JP	UMGi120-A.8	Induced pluripotent stem cell	Male
CVCL_A4JQ	UMGi120-A.15	Induced pluripotent stem cell	Male
CVCL_A7KP	SCVIi009-A	Induced pluripotent stem cell	Female
CVCL_A7KQ	SCVIi010-A	Induced pluripotent stem cell	Male
CVCL_A7KR	SCVIi011-A	Induced pluripotent stem cell	Female
CVCL_A9XX	WAe009-A-43	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT00701077	PHASE3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	PHASE3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)