Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGH5XJC)

• DOT Name: Kelch repeat and BTB domain-containing protein 2 (KBTBD2)
• Synonyms: BTB and kelch domain-containing protein 1
• Gene Name: KBTBD2
• UniProt ID: KBTB2_HUMAN
• PDB ID: 8GQ6; 8H33; 8H34; 8H35; 8H36; 8H37; 8H38; 8H3A; 8H3F; 8H3R
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MSTQDERQINTEYAVSLLEQLKLFYEQQLFTDIVLIVEGTEFPCHKMVLATCSSYFRAMF
  MSGLSESKQTHVHLRNVDAATLQIIITYAYTGNLAMNDSTVEQLYETACFLQVEDVLQRC
  REYLIKKINAENCVRLLSFADLFSCEELKQSAKRMVEHKFTAVYHQDAFMQLSHDLLIDI
  LSSDNLNVEKEETVREAAMLWLEYNTESRSQYLSSVLSQIRIDALSEVTQRAWFQGLPPN
  DKSVVVQGLYKSMPKFFKPRLGMTKEEMMIFIEASSENPCSLYSSVCYSPQAEKVYKLCS
  PPADLHKVGTVVTPDNDIYIAGGQVPLKNTKTNHSKTSKLQTAFRTVNCFYWFDAQQNTW
  FPKTPMLFVRIKPSLVCCEGYIYAIGGDSVGGELNRRTVERYDTEKDEWTMVSPLPCAWQ
  WSAAVVVHDCIYVMTLNLMYCYFPRSDSWVEMAMRQTSRSFASAAAFGDKIFYIGGLHIA
  TNSGIRLPSGTVDGSSVTVEIYDVNKNEWKMAANIPAKRYSDPCVRAVVISNSLCVFMRE
  THLNERAKYVTYQYDLELDRWSLRQHISERVLWDLGRDFRCTVGKLYPSCLEESPWKPPT
  YLFSTDGTEEFELDGEMVALPPV
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of the insulin signaling pathway, modulating insulin sensitivity by limiting PIK3R1/p85alpha abundance in adipocytes. Targets PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), for 'Lys-48'-linked polyubiquitination and proteasome-mediated degradation.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[6]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[9]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Kelch repeat and BTB domain-containing protein 2 (KBTBD2).	[12]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.