Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5HFZXU)

• DOT Name: BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10)
• Synonyms: hBACURD3; BTB/POZ domain-containing protein KCTD10; Potassium channel tetramerization domain-containing protein 10
• Gene Name: KCTD10
• Related Disease:
  HER2/NEU overexpressing breast cancer
  Gastrointestinal stromal tumour
  Neoplasm
  Hepatocellular carcinoma
  Congenital heart disease
  Coronary atherosclerosis
  Coronary heart disease
  Methylmalonic acidemia
  Vitamin B12 deficiency
• UniProt ID: BACD3_HUMAN
• PDB ID: 5FTA
• Pfam ID: PF02214
• Sequence:
  MEEMSGESVVSSAVPAAATRTTSFKGTSPSSKYVKLNVGGALYYTTMQTLTKQDTMLKAM
  FSGRMEVLTDSEGWILIDRCGKHFGTILNYLRDGAVPLPESRREIEELLAEAKYYLVQGL
  VEECQAALQNKDTYEPFCKVPVITSSKEEQKLIATSNKPAVKLLYNRSNNKYSYTSNSDD
  NMLKNIELFDKLSLRFNGRVLFIKDVIGDEICCWSFYGQGRKIAEVCCTSIVYATEKKQT
  KVEFPEARIYEETLNILLYEAQDGRGPDNALLEATGGAAGRSHHLDEDEERERIERVRRI
  HIKRPDDRAHLHQ
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex. The BCR(BACURD3) E3 ubiquitin ligase complex mediates the ubiquitination of target proteins, leading to their degradation by the proteasome.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
HER2/NEU overexpressing breast cancer	DISYKID5	Definitive	Biomarker	[1]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Disputed	Biomarker	[3]
Congenital heart disease	DISQBA23	Limited	Biomarker	[4]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[5]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[5]
Methylmalonic acidemia	DISHY8VB	Limited	Genetic Variation	[5]
Vitamin B12 deficiency	DIS91UJ1	Limited	Genetic Variation	[5]

10 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 adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[12]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 3 (KCTD10).	[16]

References

• [1] Cullin-3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2-positive breast cancer cells.Cancer Sci. 2019 Feb;110(2):650-661. doi: 10.1111/cas.13899. Epub 2019 Jan 8.
• [2] Gene expression network analysis of ETV1 reveals KCTD10 as a novel prognostic biomarker in gastrointestinal stromal tumor.PLoS One. 2013 Aug 19;8(8):e73896. doi: 10.1371/journal.pone.0073896. eCollection 2013.
• [3] Cullin-3/KCTD10 complex is essential for K27-polyubiquitination of EIF3D in human hepatocellular carcinoma HepG2 cells.Biochem Biophys Res Commun. 2019 Sep 3;516(4):1116-1122. doi: 10.1016/j.bbrc.2019.07.010. Epub 2019 Jul 5.
• [4] Downregulation of microRNA-592 protects mice from hypoplastic heart and congenital heart disease by inhibition of the Notch signaling pathway through upregulating KCTD10.J Cell Physiol. 2019 May;234(5):6033-6041. doi: 10.1002/jcp.27190. Epub 2018 Nov 27.
• [5] Association of KCTD10, MVK, and MMAB polymorphisms with dyslipidemia and coronary heart disease in Han Chinese population.Lipids Health Dis. 2016 Oct 4;15(1):171. doi: 10.1186/s12944-016-0348-7.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.