Target Information

Target General Information

Target ID

T76914 (Former ID: TTDR00903)

Target Name

Voltage-gated potassium channel Kv1.3 (KCNA3)

Synonyms

Voltage-gated potassium channel subunit Kv1.3; Voltage-gated Kv1.3 K(+) channel; Voltage-gated K(+) channel Kv1.3; Potassium channel Kv1.3; KCNA3; HuKIII; HPCN3; HLK3; HGK5

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Gene Name

KCNA3

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Idiopathic inflammatory myopathy [ICD-11: 4A41]

Psoriasis [ICD-11: EA90]

Psoriatic arthritis [ICD-11: FA21]

Function

Mediates the voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient.

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BioChemical Class

Voltage-gated ion channel

UniProt ID

KCNA3_HUMAN

Sequence

MDERLSLLRSPPPPSARHRAHPPQRPASSGGAHTLVNHGYAEPAAGRELPPDMTVVPGDH
LLEPEVADGGGAPPQGGCGGGGCDRYEPLPPSLPAAGEQDCCGERVVINISGLRFETQLK
TLCQFPETLLGDPKRRMRYFDPLRNEYFFDRNRPSFDAILYYYQSGGRIRRPVNVPIDIF
SEEIRFYQLGEEAMEKFREDEGFLREEERPLPRRDFQRQVWLLFEYPESSGPARGIAIVS
VLVILISIVIFCLETLPEFRDEKDYPASTSQDSFEAAGNSTSGSRAGASSFSDPFFVVET
LCIIWFSFELLVRFFACPSKATFSRNIMNLIDIVAIIPYFITLGTELAERQGNGQQAMSL
AILRVIRLVRVFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVILFSSAVYFAE
ADDPTSGFSSIPDAFWWAVVTMTTVGYGDMHPVTIGGKIVGSLCAIAGVLTIALPVPVIV
SNFNYFYHRETEGEEQSQYMHVGSCQHLSSSAEELRKARSNSTLSKSEYMVIEEGGMNHS
AFPQTPFKTGNSTATCTTNNNPNSCVNIKKIFTDV

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3D Structure

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AlphaFold

HIT2.0 ID

T48QK5

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

Dalazatide

Drug Info

Phase 1b/2a

Inclusion body myositis

[2]

Debio-0824

Drug Info

Phase 1b/2a

Psoriasis vulgaris

[2]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

UK-78282

Drug Info

Terminated

Inflammation

[3]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 10 Inhibitor drugs

Dalazatide

Drug Info

[4]

Debio-0824

Drug Info

[1]

UK-78282

Drug Info

[5]

1-Benzyl-7-chloro-4-hexyloxy-quinolinium

Drug Info

[6]

2-Methoxy-N-(3-methyl-2-phenyl-butyl)-benzamide

Drug Info

[7]

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

Drug Info

[8], [9]

5-(4-Phenylbutoxy)psoralen

Drug Info

[10], [11]

Correloid

Drug Info

[12]

CP-339818

Drug Info

[5]

[1-Benzyl-1H-quinolin-(4E)-ylidene]-hexyl-amine

Drug Info

[6]

Blocker (channel blocker)

[+] 2 Blocker (channel blocker) drugs

correolide

Drug Info

[13]

[14C]TEA

Drug Info

[14]

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 >>	36.364 (20/55)	5.42E-04
Calcium-activated potassium channel KCa2.3 (KCNN3)	PF02888 ; PF07885 ; PF03530 More >>	28.431 (29/102)	4.00E-03
Calcium-activated potassium channel KCa2.2 (KCNN2)	PF02888 ; PF07885 ; PF03530 More >>	38.710 (24/62)	4.00E-03

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.99E-01	Radiality	1.34E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	6.90E+01	Topological coefficient	1.00E+00	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

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 Affiliated Biological Pathways

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Reactome

[+] 1 Reactome Pathways

Voltage gated Potassium channels

WikiPathways

[+] 2 WikiPathways

Potassium Channels

BDNF signaling pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease. J Pharmacol Exp Ther. 2012 September; 342(3): 642-653.

REF 2

Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009179)

REF 4

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 5

Angular methoxy-substituted furo- and pyranoquinolinones as blockers of the voltage-gated potassium channel Kv1.3. J Med Chem. 2001 Apr 12;44(8):1249-56.

REF 6

Novel inhibitors of potassium ion channels on human T lymphocytes. J Med Chem. 1995 May 26;38(11):1877-83.

REF 7

Benzamide derivatives as blockers of Kv1.3 ion channel. Bioorg Med Chem Lett. 2003 Mar 24;13(6):1161-4.

REF 8

Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Mol Pharmacol. 2005 Nov;68(5):1254-70.

REF 9

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 10

Kv1.3-blocking 5-phenylalkoxypsoralens: a new class of immunomodulators. Mol Pharmacol. 2004 Jun;65(6):1364-74.

REF 11

N-{3-[(1,1-dioxido-1,2-benzothiazol-3-yl)(phenyl)amino]propyl}benzamide analogs as potent Kv1.3 inhibitors. Part 1. Bioorg Med Chem Lett. 2010 Dec 1;20(23):6983-8.

REF 12

Potent Kv1.3 inhibitors from correolide-modification of the C18 position. Bioorg Med Chem Lett. 2005 Jan 17;15(2):447-51.

REF 13

Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kv1.3. Biochemistry. 1999 Apr 20;38(16):4922-30.

REF 14

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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