Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI3TK38)

• DOT Name: Ankyrin repeat and SOCS box protein 3 (ASB3)
• Synonyms: ASB-3
• Gene Name: ASB3
• Related Disease:
  Anorexia nervosa cachexia
  Colorectal carcinoma
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Stroke
• UniProt ID: ASB3_HUMAN
• Pfam ID: PF00023 ; PF12796 ; PF07525
• Sequence:
  MDFTEAYADTCSTVGLAAREGNVKVLRKLLKKGRSVDVADNRGWMPIHEAAYHNSVECLQ
  MLINADSSENYIKMKTFEGFCALHLAASQGHWKIVQILLEAGADPNATTLEETTPLFLAV
  ENGQIDVLRLLLQHGANVNGSHSMCGWNSLHQASFQENAEIIKLLLRKGANKECQDDFGI
  TPLFVAAQYGKLESLSILISSGANVNCQALDKATPLFIAAQEGHTKCVELLLSSGADPDL
  YCNEDSWQLPIHAAAQMGHTKILDLLIPLTNRACDTGLNKVSPVYSAVFGGHEDCLEILL
  RNGYSPDAQACLVFGFSSPVCMAFQKDCEFFGIVNILLKYGAQINELHLAYCLKYEKFSI
  FRYFLRKGCSLGPWNHIYEFVNHAIKAQAKYKEWLPHLLVAGFDPLILLCNSWIDSVSID
  TLIFTLEFTNWKTLAPAVERMLSARASNAWILQQHIATVPSLTHLCRLEIRSSLKSERLR
  SDSYISQLPLPRSLHNYLLYEDVLRMYEVPELAAIQDG
• Function: Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes TNFRSF1B.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anorexia nervosa cachexia	DISFO5RQ	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[4]
Stroke	DISX6UHX	moderate	Genetic Variation	[5]

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 Ankyrin repeat and SOCS box protein 3 (ASB3).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Ankyrin repeat and SOCS box protein 3 (ASB3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ankyrin repeat and SOCS box protein 3 (ASB3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ankyrin repeat and SOCS box protein 3 (ASB3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ankyrin repeat and SOCS box protein 3 (ASB3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ankyrin repeat and SOCS box protein 3 (ASB3).	[9]

References

• [1] Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.Nat Genet. 2019 Aug;51(8):1207-1214. doi: 10.1038/s41588-019-0439-2. Epub 2019 Jul 15.
• [2] The loss-of-function mutations and down-regulated expression of ASB3 gene promote the growth and metastasis of colorectal cancer cells.Chin J Cancer. 2017 Jan 14;36(1):11. doi: 10.1186/s40880-017-0180-0.
• [3] ASB3 knockdown promotes mitochondrial apoptosis via activating the interdependent cleavage of Beclin1 and caspase-8 in hepatocellular carcinoma.Sci China Life Sci. 2019 Dec;62(12):1692-1702. doi: 10.1007/s11427-018-9505-0. Epub 2019 Apr 15.
• [4] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [5] Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.Lancet Neurol. 2012 Nov;11(11):951-62. doi: 10.1016/S1474-4422(12)70234-X. Epub 2012 Oct 5.
• [6] 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.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.