Target Information

Target General Information

Target ID

T17569 (Former ID: TTDC00303)

Target Name

Voltage-gated potassium channel Kv1.5 (KCNA5)

Synonyms

Voltage-gatedpotassium channel subunit Kv1.5; Voltage-gated potassium channel subunit Kv1.5; Voltage-gated potassium channel HK2; Potassium voltage-gated channel subfamily A member 5; Potassium channel Kv1.5; HPCN1; HK2; 02-Sensitive Potassium Channel Kv1.5

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Gene Name

KCNA5

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Angina pectoris [ICD-11: BA40]

Function

Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. Homotetrameric channels display rapid activation and slow inactivation. May play a role in regulating the secretion of insulin in normal pancreatic islets. Isoform 2 exhibits a voltage-dependent recovery from inactivation and an excessive cumulative inactivation. Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.

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BioChemical Class

Voltage-gated ion channel

UniProt ID

KCNA5_HUMAN

Sequence

MEIALVPLENGGAMTVRGGDEARAGCGQATGGELQCPPTAGLSDGPKEPAPKGRGAQRDA
DSGVRPLPPLPDPGVRPLPPLPEELPRPRRPPPEDEEEEGDPGLGTVEDQALGTASLHHQ
RVHINISGLRFETQLGTLAQFPNTLLGDPAKRLRYFDPLRNEYFFDRNRPSFDGILYYYQ
SGGRLRRPVNVSLDVFADEIRFYQLGDEAMERFREDEGFIKEEEKPLPRNEFQRQVWLIF
EYPESSGSARAIAIVSVLVILISIITFCLETLPEFRDERELLRHPPAPHQPPAPAPGANG
SGVMAPPSGPTVAPLLPRTLADPFFIVETTCVIWFTFELLVRFFACPSKAGFSRNIMNII
DVVAIFPYFITLGTELAEQQPGGGGGGQNGQQAMSLAILRVIRLVRVFRIFKLSRHSKGL
QILGKTLQASMRELGLLIFFLFIGVILFSSAVYFAEADNQGTHFSSIPDAFWWAVVTMTT
VGYGDMRPITVGGKIVGSLCAIAGVLTIALPVPVIVSNFNYFYHRETDHEEPAVLKEEQG
TQSQGPGLDRGVQRKVSGSRGSFCKAGGTLENADSARRGSCPLEKCNVKAKSNVDLRRSL
YALCLDTSRETDL

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3D Structure

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AlphaFold

HIT2.0 ID

T16FLN

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Dronedarone

Drug Info

Approved

Angina pectoris

[2], [3]

Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

BMS-919373

Drug Info

Phase 2

Atrial fibrillation

[4]

BMS-394136

Drug Info

Phase 1

Arrhythmia

[5]

IQB-9302

Drug Info

Phase 1

Pain

[6]

XEN-D0101

Drug Info

Phase 1

Atrial fibrillation

[7]

XEN-D0103

Drug Info

Phase 1

Atrial fibrillation

[8]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

T-226296

Drug Info

Preclinical

Obesity

[9], [10]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

Zatebradine

Drug Info

Terminated

Angina pectoris

[11], [12]

Mode of Action

[+] 6 Modes of Action

Blocker

[+] 5 Blocker drugs

Dronedarone

Drug Info

[1]

T-226296

Drug Info

[1]

NIP-142

Drug Info

[1]

RS-100302

Drug Info

[1]

S-9947

Drug Info

[1]

Inhibitor

[+] 15 Inhibitor drugs

BMS-919373

Drug Info

[13]

XEN-D0103

Drug Info

[16]

2-amino-2-phenyl-1,1-di(pyridin-3-yl)ethanol

Drug Info

[18]

2-morpholino-1,1,2-triphenylethanol

Drug Info

[18]

2-morpholino-1,1-di(pyridin-3-yl)hexan-1-ol

Drug Info

[18]

2-morpholino-1,1-di(pyridin-3-yl)octan-1-ol

Drug Info

[18]

2-morpholino-2-phenyl-1,1-di(pyridin-3-yl)ethanol

Drug Info

[18]

2-phenoxy-1-(2-p-tolylthiazolidin-3-yl)ethanone

Drug Info

[19]

2-phenyl-1,1-di(pyridin-3-yl)ethanol

Drug Info

[18]

3-(4-methoxybenzyloxy)-2-phenylthiazolidin-4-one

Drug Info

[19]

3-(benzyloxy)-2-(4-chlorophenyl)thiazolidin-4-one

Drug Info

[19]

3-methyl-2-morpholino-1,1-diphenylbutan-1-ol

Drug Info

[18]

4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromen-7-one

Drug Info

[20]

N-Benzyl-2-(toluene-4-sulfonylamino)-benzamide

Drug Info

[22]

N-Phenethyl-2-(toluene-4-sulfonylamino)-benzamide

Drug Info

[22]

Modulator

[+] 3 Modulator drugs

BMS-394136

Drug Info

[14]

XEN-D0101

Drug Info

[15]

Zatebradine

Drug Info

[17]

Opener

[+] 2 Opener drugs

IQB-9302

Drug Info

[6]

XEN-D0104

Drug Info

[16]

Blocker (channel blocker)

[+] 2 Blocker (channel blocker) drugs

clofilium

Drug Info

[21]

[14C]TEA

Drug Info

[23]

Antagonist

[+] 1 Antagonist drugs

DPO-1

Drug Info

[16]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Calcium-activated potassium channel KCa3.1 (KCNN4)	PF02888 ; PF07885 ; PF03530 More >>	30.159 (38/126)	7.40E-05
Calcium-activated potassium channel KCa2.3 (KCNN3)	PF02888 ; PF07885 ; PF03530 More >>	32.500 (26/80)	3.00E-03
Potassium channel subfamily K member 10 (KCNK10)	PF07885	40.000 (20/50)	4.00E-03

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	7.90E-05
Closeness centrality	1.96E-01	Radiality	1.34E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	1.27E+01	Topological coefficient	3.65E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Muscle/Heart Contraction

Reactome

[+] 1 Reactome Pathways

Voltage gated Potassium channels

WikiPathways

[+] 1 WikiPathways

Potassium Channels

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

New antiarrhythmic agents for atrial fibrillation and atrial flutter. Expert Opin Emerg Drugs. 2005 May;10(2):311-22.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7465).

REF 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 4

ClinicalTrials.gov (NCT02156076) A Blinded Study to Evaluate Effect on Atrial Fibrillation Burden in Patients With Paroxysmal Atrial Fibrillation. U.S. National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT00162448) A Phase I Study to Assess the Electrophysiologic Effects of BMS-394136 on the Atrium and Ventricle in Patients With Dual-Chamber Pacemakers or Defibrillators. U.S. National Institutes of Health.

REF 6

Stereoselective effects of the enantiomers of a new local anaesthetic, IQB-9302, on a human cardiac potassium channel (Kv1.5). Br J Pharmacol. 2001 Jan;132(2):385-92.

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018084)

REF 8

ClinicalTrials.gov (NCT02390258) Fed-Fasted, Single and Multiple Ascending Dose Trial of XEN-D0103. U.S. National Institutes of Health.

REF 9

REF 10

Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.

REF 11

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000429)

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035504)

REF 14

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 15

Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. J Cardiovasc Pharmacol. 2013 May;61(5):408-15.

REF 16

REF 17

DOI: 10.1161/01.CIR.94.3.562

REF 18

Discovery of triarylethanolamine inhibitors of the Kv1.5 potassium channel. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2493-6.

REF 19

Evolution of thiazolidine-based blockers of human Kv1.5 for the treatment of atrial arrhythmias. Bioorg Med Chem Lett. 2007 Jan 1;17(1):282-4.

REF 20

Substituted N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 ion channel blockers. Part 2. Bioorg Med Chem Lett. 2010 Dec 1;20(23):6989-92.

REF 21

Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel. Mol Pharmacol. 1995 Jan;47(1):198-205.

REF 22

Pharmacophore-based search, synthesis, and biological evaluation of anthranilic amides as novel blockers of the Kv1.5 channel. Bioorg Med Chem Lett. 2004 Jun 7;14(11):2823-7.

REF 23

Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol Pharmacol. 1994 Jun;45(6):1227-34.

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