Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPYKT4Z)

• DOT Name: BTB/POZ domain-containing protein KCTD12 (KCTD12)
• Synonyms: Pfetin; Predominantly fetal expressed T1 domain
• Gene Name: KCTD12
• Related Disease:
  Advanced cancer
  Lung cancer
  Neoplasm
  Adenocarcinoma
  Bipolar disorder
  Esophageal squamous cell carcinoma
  Gastrointestinal stromal tumour
  Melanoma
  Mood disorder
  Schizophrenia
  Uveal Melanoma
  Colon cancer
  Colon carcinoma
  Hepatitis B virus infection
• UniProt ID: KCD12_HUMAN
• PDB ID: 6M8S; 6QZL
• Pfam ID: PF02214
• Sequence:
  MALADSTRGLPNGGGGGGGSGSSSSSAEPPLFPDIVELNVGGQVYVTRRCTVVSVPDSLL
  WRMFTQQQPQELARDSKGRFFLDRDGFLFRYILDYLRDLQLVLPDYFPERSRLQREAEYF
  ELPELVRRLGAPQQPGPGPPPSRRGVHKEGSLGDELLPLGYSEPEQQEGASAGAPSPTLE
  LASRSPSGGAAGPLLTPSQSLDGSRRSGYITIGYRGSYTIGRDAQADAKFRRVARITVCG
  KTSLAKEVFGDTLNESRDPDRPPERYTSRYYLKFNFLEQAFDKLSESGFHMVACSSTGTC
  AFASSTDQSEDKIWTSYTEYVFCRE
• Function: Auxiliary subunit of GABA-B receptors that determine the pharmacology and kinetics of the receptor response. Increases agonist potency and markedly alter the G-protein signaling of the receptors by accelerating onset and promoting desensitization.
• Tissue Specificity: Present in a variety of fetal organs, with highest expression levels in the cochlea and brain and, in stark contrast, is detected only at extremely low levels in adult organs, such as brain and lung.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Altered Expression	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[2]
Mood disorder	DISLVMWO	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Uveal Melanoma	DISA7ZGL	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	moderate	Biomarker	[8]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[8]
Hepatitis B virus infection	DISLQ2XY	moderate	Biomarker	[8]

30 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 BTB/POZ domain-containing protein KCTD12 (KCTD12).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[20]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[21]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[22]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[24]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[25]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[26]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[27]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[28]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[23]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[33]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[34]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of BTB/POZ domain-containing protein KCTD12 (KCTD12).	[36]

References

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• [2] Downregulation of KCTD12 contributes to melanoma stemness by modulating CD271.Cancer Biol Med. 2019 Aug;16(3):498-513. doi: 10.20892/j.issn.2095-3941.2019.0073.
• [3] Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis.Mol Cell Proteomics. 2017 Mar;16(3):407-427. doi: 10.1074/mcp.M116.062273. Epub 2017 Jan 4.
• [4] Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders.Transl Psychiatry. 2015 Feb 17;5(2):e510. doi: 10.1038/tp.2015.8.
• [5] Contribution of KCTD12 to esophageal squamous cell carcinoma.BMC Cancer. 2018 Aug 29;18(1):853. doi: 10.1186/s12885-018-4765-z.
• [6] Insights into the Proteome of Gastrointestinal Stromal Tumors-Derived Exosomes Reveals New Potential Diagnostic Biomarkers.Mol Cell Proteomics. 2018 Mar;17(3):495-515. doi: 10.1074/mcp.RA117.000267. Epub 2017 Dec 14.
• [7] Lentiviral-mediated overexpression of KCTD12 inhibits the proliferation of human uveal melanoma OCM-1 cells.Oncol Rep. 2017 Feb;37(2):871-878. doi: 10.3892/or.2016.5325. Epub 2016 Dec 16.
• [8] Adefovir dipivoxil sensitizes colon cancer cells to vemurafenib by disrupting the KCTD12-CDK1 interaction.Cancer Lett. 2019 Jun 1;451:79-91. doi: 10.1016/j.canlet.2019.02.050. Epub 2019 Mar 11.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [12] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [16] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [17] 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.
• [18] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [19] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [20] 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.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [23] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [24] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [25] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [26] 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.
• [27] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [28] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [29] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [30] 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.
• [31] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [32] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [33] 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.
• [34] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [35] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [36] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.