Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSKZ1KM)

• DOT Name: BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13)
• Synonyms: hBACURD1; BTB/POZ domain-containing protein KCTD13; Polymerase delta-interacting protein 1; TNFAIP1-like protein
• Gene Name: KCTD13
• Related Disease:
  Schizophrenia
  Autism
  Isolated congenital microcephaly
  Autism spectrum disorder
  Megalencephaly
  Neurodevelopmental disorder
  Pervasive developmental disorder
• UniProt ID: BACD1_HUMAN
• PDB ID: 4UIJ
• Pfam ID: PF02214
• Sequence:
  MSAEASGPAAAAAPSLEAPKPSGLEPGPAAYGLKPLTPNSKYVKLNVGGSLHYTTLRTLT
  GQDTMLKAMFSGRVEVLTDAGGWVLIDRSGRHFGTILNYLRDGSVPLPESTRELGELLGE
  ARYYLVQGLIEDCQLALQQKRETLSPLCLIPMVTSPREEQQLLASTSKPVVKLLHNRSNN
  KYSYTSTSDDNLLKNIELFDKLALRFHGRLLFLKDVLGDEICCWSFYGQGRKIAEVCCTS
  IVYATEKKQTKVEFPEARIFEETLNILIYETPRGPDPALLEATGGAAGAGGAGRGEDEEN
  REHRVRRIHVRRHITHDERPHGQQIVFKD
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for synaptic transmission. The BCR(KCTD13) E3 ubiquitin ligase complex mediates the ubiquitination of RHOA, leading to its degradation by the proteasome Degradation of RHOA regulates the actin cytoskeleton and promotes synaptic transmission.
• Tissue Specificity: Expressed in a wide variety of tissues.
• Reactome Pathway:
  RND2 GTPase cycle (R-HSA-9696270)
  RND3 GTPase cycle (R-HSA-9696264)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]
Autism	DISV4V1Z	moderate	Biomarker	[2]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[2]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[1]
Megalencephaly	DISYW5SV	Limited	Biomarker	[1]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[1]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[13]

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 BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 (KCTD13).	[10]

References

• [1] CRISPR/Cas9-mediated Knockout of the Neuropsychiatric Risk Gene KCTD13 Causes Developmental Deficits in Human Cortical Neurons Derived from Induced Pluripotent Stem Cells.Mol Neurobiol. 2020 Feb;57(2):616-634. doi: 10.1007/s12035-019-01727-1. Epub 2019 Aug 11.
• [2] KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.Nature. 2012 May 16;485(7398):363-7. doi: 10.1038/nature11091.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.