Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQKQ346)

• DOT Name: Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4)
• Synonyms: SK4; SKCa 4; SKCa4; IKCa1; IK1; KCa3.1; KCa4; Putative Gardos channel
• Gene Name: KCNN4
• Related Disease:
  Dehydrated hereditary stomatocytosis 2
  Dehydrated hereditary stomatocytosis
• UniProt ID: KCNN4_HUMAN
• PDB ID: 6CNM; 6CNN; 6CNO; 6D42
• Pfam ID: PF02888 ; PF07885 ; PF03530
• Sequence:
  MGGDLVLGLGALRRRKRLLEQEKSLAGWALVLAGTGIGLMVLHAEMLWFGGCSWALYLFL
  VKCTISISTFLLLCLIVAFHAKEVQLFMTDNGLRDWRVALTGRQAAQIVLELVVCGLHPA
  PVRGPPCVQDLGAPLTSPQPWPGFLGQGEALLSLAMLLRLYLVPRAVLLRSGVLLNASYR
  SIGALNQVRFRHWFVAKLYMNTHPGRLLLGLTLGLWLTTAWVLSVAERQAVNATGHLSDT
  LWLIPITFLTIGYGDVVPGTMWGKIVCLCTGVMGVCCTALLVAVVARKLEFNKAEKHVHN
  FMMDIQYTKEMKESAARVLQEAWMFYKHTRRKESHAARRHQRKLLAAINAFRQVRLKHRK
  LREQVNSMVDISKMHMILYDLQQNLSSSHRALEKQIDTLAGKLDALTELLSTALGPRQLP
  EPSQQSK
• Function: Forms a voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization which promotes calcium influx. Required for maximal calcium influx and proliferation during the reactivation of naive T-cells. Plays a role in the late stages of EGF-induced macropinocytosis.
• Tissue Specificity: Widely expressed in non-excitable tissues.
• KEGG Pathway:
  Insulin secretion (hsa04911)
  GnRH secretion (hsa04929)
  Salivary secretion (hsa04970)
  Protein digestion and absorption (hsa04974)
• Reactome Pathway: Ca2+ activated K+ channels (R-HSA-1296052)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dehydrated hereditary stomatocytosis 2	DISIAVTV	Strong	Autosomal dominant	[1]
Dehydrated hereditary stomatocytosis	DISGQT6H	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[2]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[6]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[7]
Clotrimazole	DMMFCIH	Approved	Clotrimazole decreases the activity of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[8]
Chlorzoxazone	DMCYVDT	Approved	Chlorzoxazone increases the activity of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[8]
Charybdotoxin	DMKN345	Approved	Charybdotoxin decreases the activity of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[11]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[15]
zoxazolamine	DM70TKB	Terminated	zoxazolamine increases the activity of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[8]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[17]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Intermediate conductance calcium-activated potassium channel protein 4 (KCNN4).	[16]

References

• [1] A mutation in the Gardos channel is associated with hereditary xerocytosis. Blood. 2015 Sep 10;126(11):1273-80. doi: 10.1182/blood-2015-04-642496. Epub 2015 Jul 6.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] Unique signatures of stress-induced senescent human astrocytes. Exp Neurol. 2020 Dec;334:113466. doi: 10.1016/j.expneurol.2020.113466. Epub 2020 Sep 17.
• [6] Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. Clin Cancer Res. 2007 Sep 1;13(17):5219-25. doi: 10.1158/1078-0432.CCR-07-0816.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] Functional and molecular identification of intermediate-conductance Ca(2+)-activated K(+) channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol. 2004 Jul;287(1):C125-34. doi: 10.1152/ajpcell.00488.2003. Epub 2004 Feb 25.
• [9] 4-Chlorobenzo[F]isoquinoline (CBIQ), a novel activator of CFTR and DeltaF508 CFTR. Eur J Pharmacol. 2005 Jun 1;516(2):118-24. doi: 10.1016/j.ejphar.2005.04.037.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [12] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [13] 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.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [16] 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.
• [17] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [18] 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.