Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT89U5MB)

• DOT Name: BTB/POZ domain-containing protein KCTD1 (KCTD1)
• Synonyms: Potassium channel tetramerization domain-containing protein 1
• Gene Name: KCTD1
• Related Disease:
  Scalp-ear-nipple syndrome
  Branchiooculofacial syndrome
  Breast carcinoma
  Cardiovascular disease
  Non-insulin dependent diabetes
  Aplasia cutis congenita
• UniProt ID: KCTD1_HUMAN
• PDB ID: 5BXB; 5BXD; 6S4L
• Pfam ID: PF02214 ; PF20871
• Sequence:
  MSRPLITRSPASPLNNQGIPTPAQLTKSNAPVHIDVGGHMYTSSLATLTKYPESRIGRLF
  DGTEPIVLDSLKQHYFIDRDGQMFRYILNFLRTSKLLIPDDFKDYTLLYEEAKYFQLQPM
  LLEMERWKQDRETGRFSRPCECLVVRVAPDLGERITLSGDKSLIEEVFPEIGDVMCNSVN
  AGWNHDSTHVIRFPLNGYCHLNSVQVLERLQQRGFEIVGSCGGGVDSSQFSEYVLRRELR
  RTPRVPSVIRIKQEPLD
• Function: May repress the transcriptional activity of AP-2 family members, including TFAP2A, TFAP2B and TFAP2C to various extent.
• Tissue Specificity: Expressed in mammary gland, kidney, brain and ovary.
• Reactome Pathway: Negative regulation of activity of TFAP2 (AP-2) family transcription factors (R-HSA-8866904)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Scalp-ear-nipple syndrome	DISZIT3W	Definitive	Autosomal dominant	[1]
Branchiooculofacial syndrome	DISHJ9O9	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[4]
Aplasia cutis congenita	DISMDAYM	moderate	Genetic Variation	[1]

3 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 BTB/POZ domain-containing protein KCTD1 (KCTD1).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of BTB/POZ domain-containing protein KCTD1 (KCTD1).	[15]

References

• [1] Mutations in KCTD1 cause scalp-ear-nipple syndrome. Am J Hum Genet. 2013 Apr 4;92(4):621-6. doi: 10.1016/j.ajhg.2013.03.002. Epub 2013 Mar 28.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease.BMC Cardiovasc Disord. 2011 Jun 10;11:29. doi: 10.1186/1471-2261-11-29.
• [4] No clinical utility of common polymorphisms in IGF1, IRS1, GCKR, PPARG, GCK1 and KCTD1 genes previously associated with insulin resistance in overweight children from Romania and Moldova.J Pediatr Endocrinol Metab. 2019 Jan 28;32(1):33-39. doi: 10.1515/jpem-2018-0288.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] 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.
• [8] 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.
• [9] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] 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.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] 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.