Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFTL0BQ)

• DOT Name: Potassium channel subfamily T member 2 (KCNT2)
• Synonyms: Sequence like an intermediate conductance potassium channel subunit; Sodium and chloride-activated ATP-sensitive potassium channel Slo2.1
• Gene Name: KCNT2
• Related Disease: Developmental and epileptic encephalopathy, 57
• UniProt ID: KCNT2_HUMAN
• Pfam ID: PF03493 ; PF07885
• Sequence:
  MVDLESEVPPLPPRYRFRDLLLGDQGWQNDDRVQVEFYMNENTFKERLKLFFIKNQRSSL
  RIRLFNFSLKLLSCLLYIIRVLLENPSQGNEWSHIFWVNRSLPLWGLQVSVALISLFETI
  LLGYLSYKGNIWEQILRIPFILEIINAVPFIISIFWPSLRNLFVPVFLNCWLAKHALENM
  INDLHRAIQRTQSAMFNQVLILISTLLCLIFTCICGIQHLERIGKKLNLFDSLYFCIVTF
  STVGFGDVTPETWSSKLFVVAMICVALVVLPIQFEQLAYLWMERQKSGGNYSRHRAQTEK
  HVVLCVSSLKIDLLMDFLNEFYAHPRLQDYYVVILCPTEMDVQVRRVLQIPMWSQRVIYL
  QGSALKDQDLLRAKMDDAEACFILSSRCEVDRTSSDHQTILRAWAVKDFAPNCPLYVQIL
  KPENKFHIKFADHVVCEEEFKYAMLALNCICPATSTLITLLVHTSRGQEGQQSPEQWQKM
  YGRCSGNEVYHIVLEESTFFAEYEGKSFTYASFHAHKKFGVCLIGVRREDNKNILLNPGP
  RYIMNSTDICFYINITKEENSAFKNQDQQRKSNVSRSFYHGPSRLPVHSIIASMGTVAID
  LQDTSCRSASGPTLSLPTEGSKEIRRPSIAPVLEVADTSSIQTCDLLSDQSEDETTPDEE
  MSSNLEYAKGYPPYSPYIGSSPTFCHLLHEKVPFCCLRLDKSCQHNYYEDAKAYGFKNKL
  IIVAAETAGNGLYNFIVPLRAYYRPKKELNPIVLLLDNPPDMHFLDAICWFPMVYYMVGS
  IDNLDDLLRCGVTFAANMVVVDKESTMSAEEDYMADAKTIVNVQTLFRLFSSLSIITELT
  HPANMRFMQFRAKDCYSLALSKLEKKERERGSNLAFMFRLPFAAGRVFSISMLDTLLYQS
  FVKDYMISITRLLLGLDTTPGSGFLCSMKITADDLWIRTYARLYQKLCSSTGDVPIGIYR
  TESQKLTTSESQISISVEEWEDTKDSKEQGHHRSNHRNSTSSDQSDHPLLRRKSMQWARR
  LSRKGPKHSGKTAEKITQQRLNLYRRSERQELAELVKNRMKHLGLSTVGYDEMNDHQSTL
  SYILINPSPDTRIELNDVVYLIRPDPLAYLPNSEPSRRNSICNVTGQDSREETQL
• Function: Outward rectifying potassium channel. Produces rapidly activating outward rectifier K(+) currents. Activated by high intracellular sodium and chloride levels. Channel activity is inhibited by ATP and by inhalation anesthetics, such as isoflurane. Inhibited upon stimulation of G-protein coupled receptors, such as CHRM1 and GRM1.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 57	DISY28TU	Strong	Autosomal dominant	[1]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Potassium channel subfamily T member 2 (KCNT2).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Potassium channel subfamily T member 2 (KCNT2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium channel subfamily T member 2 (KCNT2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Potassium channel subfamily T member 2 (KCNT2).	[13]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Potassium channel subfamily T member 2 (KCNT2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium channel subfamily T member 2 (KCNT2).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Potassium channel subfamily T member 2 (KCNT2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Potassium channel subfamily T member 2 (KCNT2).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Potassium channel subfamily T member 2 (KCNT2).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Potassium channel subfamily T member 2 (KCNT2).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Potassium channel subfamily T member 2 (KCNT2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium channel subfamily T member 2 (KCNT2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Potassium channel subfamily T member 2 (KCNT2).	[14]

References

• [1] A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy. Cell Rep. 2017 Oct 24;21(4):926-933. doi: 10.1016/j.celrep.2017.09.088.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.