Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG9MLO4)

• DOT Name: SPRY domain-containing SOCS box protein 4 (SPSB4)
• Synonyms: SSB-4
• Gene Name: SPSB4
• Related Disease:
  Major depressive disorder
  Mood disorder
  Stroke
• UniProt ID: SPSB4_HUMAN
• PDB ID: 2V24; 6DN7; 6DN8
• Pfam ID: PF07525 ; PF00622
• Sequence:
  MGQKLSGSLKSVEVREPALRPAKRELRGAEPGRPARLDQLLDMPAAGLAVQLRHAWNPED
  RSLNVFVKDDDRLTFHRHPVAQSTDGIRGKVGHARGLHAWQINWPARQRGTHAVVGVATA
  RAPLHSVGYTALVGSDAESWGWDLGRSRLYHDGKNQPGVAYPAFLGPDEAFALPDSLLVV
  LDMDEGTLSFIVDGQYLGVAFRGLKGKKLYPVVSAVWGHCEVTMRYINGLDPEPLPLMDL
  CRRSIRSALGRQRLQDISSLPLPQSLKNYLQYQ
• Function: Substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Negatively regulates nitric oxide (NO) production and limits cellular toxicity in activated macrophages by mediating the ubiquitination and proteasomal degradation of NOS2. Acts as a bridge which links NOS2 with the ECS E3 ubiquitin ligase complex components ELOC and CUL5. Diminishes EphB2-dependent cell repulsive responses by mediating the ubiquitination and degradation of EphB2/CTF2. Regulates cellular clock function by mediating the ubiquitin/proteasome-dependent degradation of the circadian transcriptional repressor NR1D1.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[1]
Stroke	DISX6UHX	moderate	Genetic Variation	[2]

3 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 SPRY domain-containing SOCS box protein 4 (SPSB4).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SPRY domain-containing SOCS box protein 4 (SPSB4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of SPRY domain-containing SOCS box protein 4 (SPSB4).	[7]

4 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 SPRY domain-containing SOCS box protein 4 (SPSB4).	[4]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of SPRY domain-containing SOCS box protein 4 (SPSB4).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SPRY domain-containing SOCS box protein 4 (SPSB4).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SPRY domain-containing SOCS box protein 4 (SPSB4).	[6]

References

• [1] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [2] Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.Stroke. 2014 Jan;45(1):24-36. doi: 10.1161/STROKEAHA.113.002707. Epub 2013 Nov 21.
• [3] 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.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.
• [7] 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.
• [8] 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.