Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM6L4A0)

• DOT Name: BTB/POZ domain-containing protein KCTD15 (KCTD15)
• Synonyms: Potassium channel tetramerization domain-containing protein 15
• Gene Name: KCTD15
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Cardiovascular disease
  Medulloblastoma
  Non-insulin dependent diabetes
• UniProt ID: KCD15_HUMAN
• Pfam ID: PF02214 ; PF20871
• Sequence:
  MPHRKERPSGSSLHTHGSTGTAEGGNMSRLSLTRSPVSPLAAQGIPLPAQLTKSNAPVHI
  DVGGHMYTSSLATLTKYPDSRISRLFNGTEPIVLDSLKQHYFIDRDGEIFRYVLSFLRTS
  KLLLPDDFKDFSLLYEEARYYQLQPMVRELERWQQEQEQRRRSRACDCLVVRVTPDLGER
  IALSGEKALIEEVFPETGDVMCNSVNAGWNQDPTHVIRFPLNGYCRLNSVQVLERLFQRG
  FSVAASCGGGVDSSQFSEYVLCREERRPQPTPTAVRIKQEPLD
• Function: During embryonic development, interferes with neural crest formation. Inhibits AP2 transcriptional activity by interaction with its activation domain.
• Reactome Pathway: Negative regulation of activity of TFAP2 (AP-2) family transcription factors (R-HSA-8866904)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[13]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[20]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid decreases the expression of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of BTB/POZ domain-containing protein KCTD15 (KCTD15).	[17]

References

• [1] Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: the PAGE study.Am J Epidemiol. 2013 Sep 1;178(5):780-90. doi: 10.1093/aje/kwt028. Epub 2013 Jul 2.
• [2] Obesity genotype score and cardiovascular risk in women with type 2 diabetes mellitus.Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):327-32. doi: 10.1161/ATVBAHA.109.196196. Epub 2009 Nov 12.
• [3] KCTD15 inhibits the Hedgehog pathway in Medulloblastoma cells by increasing protein levels of the oncosuppressor KCASH2.Oncogenesis. 2019 Nov 4;8(11):64. doi: 10.1038/s41389-019-0175-6.
• [4] Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese.J Clin Endocrinol Metab. 2010 May;95(5):2418-25. doi: 10.1210/jc.2009-2077. Epub 2010 Mar 9.
• [5] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] 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.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.