Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHGEE2K)

• DOT Name: SPRY domain-containing SOCS box protein 3 (SPSB3)
• Synonyms: SSB-3
• Gene Name: SPSB3
• Related Disease:
  Advanced cancer
  Esophageal squamous cell carcinoma
  Metastatic malignant neoplasm
  Short stature due to primary acid-labile subunit deficiency
• UniProt ID: SPSB3_HUMAN
• Pfam ID: PF00622
• Sequence:
  MARRPRNSRAWHFVLSAARRDADARAVALAGSTNWGYDSDGQHSDSDSDPEYSTLPPSIP
  SAVPVTGESFCDCAGQSEASFCSSLHSAHRGRDCRCGEEDEYFDWVWDDLNKSSATLLSC
  DNRKVSFHMEYSCGTAAIRGTKELGEGQHFWEIKMTSPVYGTDMMVGIGTSDVDLDKYRH
  TFCSLLGRDEDSWGLSYTGLLHHKGDKTSFSSRFGQGSIIGVHLDTWHGTLTFFKNRKCI
  GVAATKLQNKRFYPMVCSTAARSSMKVTRSCASATSLQYLCCHRLRQLRPDSGDTLEGLP
  LPPGLKQVLHNKLGWVLSMSCSRRKAPVSDPQAATSAHPSSREPRPCQRKRCRRT
• Function: May be a 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.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[1]
Short stature due to primary acid-labile subunit deficiency	DISW3WR3	Limited	Genetic Variation	[2]

2 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 SPRY domain-containing SOCS box protein 3 (SPSB3).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SPRY domain-containing SOCS box protein 3 (SPSB3).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of SPRY domain-containing SOCS box protein 3 (SPSB3).	[13]

References

• [1] SPSB3 targets SNAIL for degradation in GSK-3 phosphorylation-dependent manner and regulates metastasis.Oncogene. 2018 Feb 8;37(6):768-776. doi: 10.1038/onc.2017.370. Epub 2017 Oct 23.
• [2] Assessment of pathogenicity of natural IGFALS gene variants by in silico bioinformatics tools and invitro functional studies.Mol Cell Endocrinol. 2016 Jul 5;429:19-28. doi: 10.1016/j.mce.2016.03.031. Epub 2016 Mar 25.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.