Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCY281R)

• DOT Name: Potassium channel subfamily K member 6 (KCNK6)
• Synonyms: Inward rectifying potassium channel protein TWIK-2; TWIK-originated similarity sequence
• Gene Name: KCNK6
• Related Disease:
  Malignant soft tissue neoplasm
  Pneumonia
  Pneumonitis
  Sarcoma
• UniProt ID: KCNK6_HUMAN
• Pfam ID: PF07885
• Sequence:
  MRRGALLAGALAAYAAYLVLGALLVARLEGPHEARLRAELETLRAQLLQRSPCVAAPALD
  AFVERVLAAGRLGRVVLANASGSANASDPAWDFASALFFASTLITTVGYGYTTPLTDAGK
  AFSIAFALLGVPTTMLLLTASAQRLSLLLTHVPLSWLSMRWGWDPRRAACWHLVALLGVV
  VTVCFLVPAVIFAHLEEAWSFLDAFYFCFISLSTIGLGDYVPGEAPGQPYRALYKVLVTV
  YLFLGLVAMVLVLQTFRHVSDLHGLTELILLPPPCPASFNADEDDRVDILGPQPESHQQL
  SASSHTDYASIPR
• Function: Exhibits outward rectification in a physiological K(+) gradient and mild inward rectification in symmetrical K(+) conditions.
• Tissue Specificity: Widespread expression, detected in all tissues tested except for skeletal muscle. Strongest expression in placenta, pancreas, heart, colon and spleen, lower levels detected in peripheral blood leukocytes, lung, liver, kidney and thymus. Lowest expression detected in brain.
• Reactome Pathway:
  Phase 4 - resting membrane potential (R-HSA-5576886)
  Tandem of pore domain in a weak inwardly rectifying K+ channels (TWIK) (R-HSA-1299308)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[1]
Pneumonia	DIS8EF3M	Strong	Biomarker	[2]
Pneumonitis	DIS88E0K	Strong	Biomarker	[2]
Sarcoma	DISZDG3U	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Potassium channel subfamily K member 6 (KCNK6).	[3]

12 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 K member 6 (KCNK6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium channel subfamily K member 6 (KCNK6).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Potassium channel subfamily K member 6 (KCNK6).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Potassium channel subfamily K member 6 (KCNK6).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[14]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Potassium channel subfamily K member 6 (KCNK6).	[15]

References

• [1] Does a less intensive surveillance protocol affect the survival of patients after treatment of a sarcoma of the limb? updated results of the randomized TOSS study.Bone Joint J. 2018 Feb;100-B(2):262-268. doi: 10.1302/0301-620X.100B2.BJJ-2017-0789.R1.
• [2] The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation.Immunity. 2018 Jul 17;49(1):56-65.e4. doi: 10.1016/j.immuni.2018.04.032. Epub 2018 Jun 26.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [11] 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.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [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.
• [15] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.