Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQVTMK5)

• DOT Name: Small conductance calcium-activated potassium channel protein 2 (KCNN2)
• Synonyms: SK2; SKCa 2; SKCa2; KCa2.2
• Gene Name: KCNN2
• Related Disease: Neurodevelopmental disorder with or without variable movement or behavioral abnormalities
• UniProt ID: KCNN2_HUMAN
• PDB ID: 5V02; 5WBX; 5WC5; 6ALE
• Pfam ID: PF02888 ; PF07885 ; PF03530
• Sequence:
  MSSCRYNGGVMRPLSNLSASRRNLHEMDSEAQPLQPPASVGGGGGASSPSAAAAAAAAVS
  SSAPEIVVSKPEHNNSNNLALYGTGGGGSTGGGGGGGGSGHGSSSGTKSSKKKNQNIGYK
  LGHRRALFEKRKRLSDYALIFGMFGIVVMVIETELSWGAYDKASLYSLALKCLISLSTII
  LLGLIIVYHAREIQLFMVDNGADDWRIAMTYERIFFICLEILVCAIHPIPGNYTFTWTAR
  LAFSYAPSTTTADVDIILSIPMFLRLYLIARVMLLHSKLFTDASSRSIGALNKINFNTRF
  VMKTLMTICPGTVLLVFSISLWIIAAWTVRACERYHDQQDVTSNFLGAMWLISITFLSIG
  YGDMVPNTYCGKGVCLLTGIMGAGCTALVVAVVARKLELTKAEKHVHNFMMDTQLTKRVK
  NAAANVLRETWLIYKNTKLVKKIDHAKVRKHQRKFLQAIHQLRSVKMEQRKLNDQANTLV
  DLAKTQNIMYDMISDLNERSEDFEKRIVTLETKLETLIGSIHALPGLISQTIRQQQRDFI
  EAQMESYDKHVTYNAERSRSSSRRRRSSSTAPPTSSESS
• Function: Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization.
• Tissue Specificity: Expressed in atrial myocytes (at protein level). Widely expressed.
• KEGG Pathway:
  Serotonergic sy.pse (hsa04726)
  Insulin secretion (hsa04911)
  GnRH secretion (hsa04929)
  Bile secretion (hsa04976)
• Reactome Pathway:
  Acetylcholine inhibits contraction of outer hair cells (R-HSA-9667769)
  Ca2+ activated K+ channels (R-HSA-1296052)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with or without variable movement or behavioral abnormalities	DISJTXWX	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[8]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[9]
Tubocurarine	DMBZIVP	Approved	Tubocurarine decreases the activity of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[15]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Small conductance calcium-activated potassium channel protein 2 (KCNN2).	[14]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [5] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [9] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [10] Ca2+-activated K+ channels in human leukemic Jurkat T cells. Molecular cloning, biochemical and functional characterization. J Biol Chem. 2000 Dec 22;275(51):39954-63. doi: 10.1074/jbc.M001562200.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.