Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTW0CMT)

• DTT 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
• Gene Name: KCNA5
• DTT Type: Successful target; [1]
• BioChemical Class: Voltage-gated ion channel
• UniProt ID: KCNA5_HUMAN
• TTD ID: T17569
• Sequence:
  MEIALVPLENGGAMTVRGGDEARAGCGQATGGELQCPPTAGLSDGPKEPAPKGRGAQRDA
  DSGVRPLPPLPDPGVRPLPPLPEELPRPRRPPPEDEEEEGDPGLGTVEDQALGTASLHHQ
  RVHINISGLRFETQLGTLAQFPNTLLGDPAKRLRYFDPLRNEYFFDRNRPSFDGILYYYQ
  SGGRLRRPVNVSLDVFADEIRFYQLGDEAMERFREDEGFIKEEEKPLPRNEFQRQVWLIF
  EYPESSGSARAIAIVSVLVILISIITFCLETLPEFRDERELLRHPPAPHQPPAPAPGANG
  SGVMAPPSGPTVAPLLPRTLADPFFIVETTCVIWFTFELLVRFFACPSKAGFSRNIMNII
  DVVAIFPYFITLGTELAEQQPGGGGGGQNGQQAMSLAILRVIRLVRVFRIFKLSRHSKGL
  QILGKTLQASMRELGLLIFFLFIGVILFSSAVYFAEADNQGTHFSSIPDAFWWAVVTMTT
  VGYGDMRPITVGGKIVGSLCAIAGVLTIALPVPVIVSNFNYFYHRETDHEEPAVLKEEQG
  TQSQGPGLDRGVQRKVSGSRGSFCKAGGTLENADSARRGSCPLEKCNVKAKSNVDLRRSL
  YALCLDTSRETDL
• 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.
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dronedarone	DMA8FS5	Angina pectoris	BA40	Approved	[1]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-919373	DMN28WK	Atrial fibrillation	BC81.3	Phase 2	[2]
BMS-394136	DMGDJQR	Arrhythmia	BC9Z	Phase 1	[3]
IQB-9302	DMET0H4	Pain	MG30-MG3Z	Phase 1	[4]
XEN-D0101	DMU0V45	Atrial fibrillation	BC81.3	Phase 1	[5]
XEN-D0103	DMR0U4V	Atrial fibrillation	BC81.3	Phase 1	[6]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
T-226296	DMJ6P9U	Obesity	5B81	Preclinical	[1]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Zatebradine	DMNYKOT	Angina pectoris	BA40	Terminated	[7]

20 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-amino-2-phenyl-1,1-di(pyridin-3-yl)ethanol	DM14HCY	Discovery agent	N.A.	Investigative	[8]
2-morpholino-1,1,2-triphenylethanol	DMFHTEG	Discovery agent	N.A.	Investigative	[8]
2-morpholino-1,1-di(pyridin-3-yl)hexan-1-ol	DMH89O5	Discovery agent	N.A.	Investigative	[8]
2-morpholino-1,1-di(pyridin-3-yl)octan-1-ol	DMDMVA1	Discovery agent	N.A.	Investigative	[8]
2-morpholino-2-phenyl-1,1-di(pyridin-3-yl)ethanol	DM3V5AB	Discovery agent	N.A.	Investigative	[8]
2-phenoxy-1-(2-p-tolylthiazolidin-3-yl)ethanone	DMQX7FW	Discovery agent	N.A.	Investigative	[9]
2-phenyl-1,1-di(pyridin-3-yl)ethanol	DMERNSK	Discovery agent	N.A.	Investigative	[8]
3-(4-methoxybenzyloxy)-2-phenylthiazolidin-4-one	DMFRZGS	Discovery agent	N.A.	Investigative	[9]
3-(benzyloxy)-2-(4-chlorophenyl)thiazolidin-4-one	DMD4WHN	Discovery agent	N.A.	Investigative	[9]
3-methyl-2-morpholino-1,1-diphenylbutan-1-ol	DMKWAV6	Discovery agent	N.A.	Investigative	[8]
4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromen-7-one	DMKMH5L	Discovery agent	N.A.	Investigative	[10]
clofilium	DMQ37OP	Discovery agent	N.A.	Investigative	[11]
DPO-1	DMHCZP0	Atrial fibrillation	BC81.3	Investigative	[6]
N-Benzyl-2-(toluene-4-sulfonylamino)-benzamide	DM3C0P2	Discovery agent	N.A.	Investigative	[12]
N-Phenethyl-2-(toluene-4-sulfonylamino)-benzamide	DM1BU5P	Discovery agent	N.A.	Investigative	[12]
NIP-142	DMV53PH	Atrial fibrillation	BC81.3	Investigative	[1]
RS-100302	DM63NGW	Atrial fibrillation	BC81.3	Investigative	[1]
S-9947	DMHB6UY	Atrial fibrillation	BC81.3	Investigative	[1]
XEN-D0104	DM1EHG5	Atrial fibrillation	BC81.3	Investigative	[6]
[14C]TEA	DM6SFYH	Discovery agent	N.A.	Investigative	[13]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Voltage-gated potassium channel subunit Kv1.5 (KCNA5) DTP Info
• Gene Name: KCNA5

References

• [1] New antiarrhythmic agents for atrial fibrillation and atrial flutter. Expert Opin Emerg Drugs. 2005 May;10(2):311-22.
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035504)
• [3] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [4] 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.
• [5] 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.
• [6] 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. (Target id: 542).
• [7] DOI: 10.1161/01.CIR.94.3.562
• [8] Discovery of triarylethanolamine inhibitors of the Kv1.5 potassium channel. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2493-6.
• [9] 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.
• [10] 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.
• [11] Mechanism of clofilium block of the human Kv1.5 delayed rectifier potassium channel. Mol Pharmacol. 1995 Jan;47(1):198-205.
• [12] 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.
• [13] 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.