Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFQ12ZJ)

• DOT Name: Kelch repeat and BTB domain-containing protein 6 (KBTBD6)
• Gene Name: KBTBD6
• UniProt ID: KBTB6_HUMAN
• PDB ID: 4XC2
• Pfam ID: PF07707 ; PF00651 ; PF20165 ; PF01344
• Sequence:
  MQSREDAPRSRRLASPRGGKRPKKIHKPTVSAFFTGPEELKDTAHSAALLAQLKSFYDAR
  LLCDVTIEVVTPGSGPGTGRLFPCNRNVLAAACPYFKSMFTGGMYESQQASVTMHDVDAE
  SFEVLVDYCYTGRVSLSEANVERLYAASDMLQLEYVREACASFLARRLDLTNCTAILKFA
  DAFGHRKLRSQAQSYIAQNFKQLSHMGSIREETLADLTLAQLLAVLRLDSLDVESEQTVC
  HVAVQWLEAAPKERGPSAAEVFKCVRWMHFTEEDQDYLEGLLTKPIVKKYCLDVIEGALQ
  MRYGDLLYKSLVPVPNSSSSSSSSNSLVSAAENPPQRLGMCAKEMVIFFGHPRDPFLCCD
  PYSGDLYKVPSPLTCLAHTRTVTTLAVCISPDHDIYLAAQPRTDLWVYKPAQNSWQQLAD
  RLLCREGMDVAYLNGYIYILGGRDPITGVKLKEVECYNVKRNQWALVAPLPHSFLSFDLM
  VIRDYLYALNSKRMFCYDPSHNMWLKCVSLKRNDFQEACVFNEEIYCICDIPVMKVYNPV
  RAEWRQMNNIPLVSETNNYRIIKHGQKLLLITSRTPQWKKNRVTVYEYDIRGDQWINIGT
  TLGLLQFDSNFFCLSARVYPSCLEPGQSFLTEEEEIPSESSTEWDLGGFSEPDSESGSSS
  SLSDDDFWVRVAPQ
• Function: As part of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex functions as a substrate adapter for the RAC1 guanine exchange factor (GEF) TIAM1, mediating its 'Lys-48' ubiquitination and proteasomal degradation. By controlling this ubiquitination, regulates RAC1 signal transduction and downstream biological processes including the organization of the cytoskeleton, cell migration and cell proliferation. Ubiquitination of TIAM1 requires the membrane-associated protein GABARAP which may restrict locally the activity of the complex.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

10 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 Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[6]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[11]

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 decreases the methylation of Kelch repeat and BTB domain-containing protein 6 (KBTBD6).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [6] 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.
• [7] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.