Target Information

Target General Information

Target ID

T54132 (Former ID: TTDC00128)

Target Name

Voltage-gated potassium channel Kv7.3 (KCNQ3)

Synonyms

Voltage-gated potassium channel subunit Kv7.3; Potassium channel alpha subunit KvLQT3; Potassium channel KQT-like 3; KQT-like 3; KCNQ3; K+ channel KCNQ3

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Gene Name

KCNQ3

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Behcet disease [ICD-11: 4A62]

Function

Probably important in the regulation of neuronal excitability. Associates with KCNQ2 or KCNQ5 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs.

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BioChemical Class

Voltage-gated ion channel

UniProt ID

KCNQ3_HUMAN

Sequence

MGLKARRAAGAAGGGGDGGGGGGGAANPAGGDAAAAGDEERKVGLAPGDVEQVTLALGAG
ADKDGTLLLEGGGRDEGQRRTPQGIGLLAKTPLSRPVKRNNAKYRRIQTLIYDALERPRG
WALLYHALVFLIVLGCLILAVLTTFKEYETVSGDWLLLLETFAIFIFGAEFALRIWAAGC
CCRYKGWRGRLKFARKPLCMLDIFVLIASVPVVAVGNQGNVLATSLRSLRFLQILRMLRM
DRRGGTWKLLGSAICAHSKELITAWYIGFLTLILSSFLVYLVEKDVPEVDAQGEEMKEEF
ETYADALWWGLITLATIGYGDKTPKTWEGRLIAATFSLIGVSFFALPAGILGSGLALKVQ
EQHRQKHFEKRRKPAAELIQAAWRYYATNPNRIDLVATWRFYESVVSFPFFRKEQLEAAS
SQKLGLLDRVRLSNPRGSNTKGKLFTPLNVDAIEESPSKEPKPVGLNNKERFRTAFRMKA
YAFWQSSEDAGTGDPMAEDRGYGNDFPIEDMIPTLKAAIRAVRILQFRLYKKKFKETLRP
YDVKDVIEQYSAGHLDMLSRIKYLQTRIDMIFTPGPPSTPKHKKSQKGSAFTFPSQQSPR
NEPYVARPSTSEIEDQSMMGKFVKVERQVQDMGKKLDFLVDMHMQHMERLQVQVTEYYPT
KGTSSPAEAEKKEDNRYSDLKTIICNYSETGPPEPPYSFHQVTIDKVSPYGFFAHDPVNL
PRGGPSSGKVQATPPSSATTYVERPTVLPILTLLDSRVSCHSQADLQGPYSDRISPRQRR
SITRDSDTPLSLMSVNHEELERSPSGFSISQDRDDYVFGPNGGSSWMREKRYLAEGETDT
DTDPFTPSGSMPLSSTGDGISDSVWTPSNKPI

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3D Structure

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AlphaFold

HIT2.0 ID

T64E5V

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Retigabine

Drug Info

Approved

Behcet disease

[2]

Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

Linopirdine

Drug Info

Phase 3

Cognitive impairment

[1], [3]

ICA-105665

Drug Info

Phase 2

Epilepsy

[4]

XEN1101

Drug Info

Phase 1

Epilepsy

[5]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

ICA-69673

Drug Info

Preclinical

Pain

[6]

Mode of Action

[+] 4 Modes of Action

Modulator

[+] 3 Modulator drugs

Retigabine

Drug Info

[7], [8], [9]

Linopirdine

Drug Info

[1]

ICA-69673

Drug Info

[11]

Activator

[+] 2 Activator drugs

ICA-105665

Drug Info

[10]

XEN1101

Drug Info

[5]

Inhibitor

[+] 1 Inhibitor drugs

PD-32577

Drug Info

[12]

Blocker (channel blocker)

[+] 1 Blocker (channel blocker) drugs

[14C]TEA

Drug Info

[13]

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). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). 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 Human Pathway Affiliation 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).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

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

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Calcium-activated potassium channel KCa3.1 (KCNN4)	PF02888 ; PF07885 ; PF03530 More >>	30.337 (27/89)	1.95E-06
Calcium-activated potassium channel KCa2.3 (KCNN3)	PF02888 ; PF07885 ; PF03530 More >>	22.951 (28/122)	1.07E-04
Calcium-activated potassium channel KCa2.1 (KCNN1)	PF02888 ; PF07885 ; PF03530 More >>	24.590 (30/122)	1.41E-04
Calcium-activated potassium channel KCa2.2 (KCNN2)	PF02888 ; PF07885 ; PF03530 More >>	28.889 (26/90)	4.84E-04
Calcium-activated potassium channel KCa4.2 (KCNT2)	PF03493 ; PF07885	29.870 (23/77)	6.69E-04
Calcium-activated potassium channel KCa4.1 (KCNT1)	PF03493 ; PF07885	28.395 (23/81)	5.00E-03
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KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Cholinergic synapse	hsa04725	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.52E-01	Radiality	1.20E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	9.00E+00	Topological coefficient	1.00E+00	Eccentricity	14
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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Cholinergic synapse

Reactome

[+] 2 Reactome Pathways

Voltage gated Potassium channels

Interaction between L1 and Ankyrins

WikiPathways

[+] 2 WikiPathways

Potassium Channels

L1CAM interactions

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

The M-channel blocker linopirdine is an agonist of the capsaicin receptor TRPV1. J Pharmacol Sci. 2010;114(3):332-40.

REF 2

Clinical pipeline report, company report or official report of GlaxoSmithKline.

REF 3

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: 2599).

REF 4

Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy. Epilepsia. 2013 Aug;54(8):1437-43.

REF 5

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

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011004)

REF 7

The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels. Epilepsia. 2012 Apr;53(4):606-12.

REF 8

2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.

REF 9

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia. 2012 Mar;53(3):412-24.

REF 10

New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels. Curr Neurol Neurosci Rep. 2008 Jul;8(4):345-52.

REF 11

Voltage-gated Potassium Channels as Therapeutic Drug Targets

REF 12

Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.

REF 13

Differential tetraethylammonium sensitivity of KCNQ1-4 potassium channels. Br J Pharmacol. 2000 Feb;129(3):413-5.

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