Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWA9KFU)

• DOT Name: Suppressor of cytokine signaling 1 (SOCS1)
• Synonyms: SOCS-1; JAK-binding protein; JAB; STAT-induced STAT inhibitor 1; SSI-1; Tec-interacting protein 3; TIP-3
• Gene Name: SOCS1
• Related Disease:
  Autoinflammatory syndrome with immunodeficiency
  Autoimmune disease
• UniProt ID: SOCS1_HUMAN
• Pfam ID: PF00017 ; PF07525
• Sequence:
  MVAHNQVAADNAVSTAAEPRRRPEPSSSSSSSPAAPARPRPCPAVPAPAPGDTHFRTFRS
  HADYRRITRASALLDACGFYWGPLSVHGAHERLRAEPVGTFLVRDSRQRNCFFALSVKMA
  SGPTSIRVHFQAGRFHLDGSRESFDCLFELLEHYVAAPRRMLGAPLRQRRVRPLQELCRQ
  RIVATVGRENLARIPLNPVLRDYLSSFPFQI
• Function: Essential negative regulator of type I and type II interferon (IFN) signaling, as well as that of other cytokines, including IL2, IL4, IL6 and leukemia inhibitory factor (LIF). Downregulates cytokine signaling by inhibiting the JAK/STAT signaling pathway. Acts by binding to JAK proteins and to IFNGR1 and inhibiting their kinase activity. In vitro, suppresses Tec protein-tyrosine activity. Regulates IFN-gamma (IFNG)-mediated sensory neuron survival. Probable substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
• Tissue Specificity: Expressed in all tissues with high expression in spleen, small intestine and peripheral blood leukocytes.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Osteoclast differentiation (hsa04380)
  JAK-STAT sig.ling pathway (hsa04630)
  Insulin sig.ling pathway (hsa04910)
  Prolactin sig.ling pathway (hsa04917)
  Type II diabetes mellitus (hsa04930)
  Growth hormone synthesis, secretion and action (hsa04935)
  Toxoplasmosis (hsa05145)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  Regulation of KIT signaling (R-HSA-1433559)
  MyD88 (R-HSA-166058)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Interferon gamma signaling (R-HSA-877300)
  Regulation of IFNG signaling (R-HSA-877312)
  Interferon alpha/beta signaling (R-HSA-909733)
  Regulation of IFNA/IFNB signaling (R-HSA-912694)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  Inactivation of CSF3 (G-CSF) signaling (R-HSA-9705462)
  Growth hormone receptor signaling (R-HSA-982772)
  Antigen processing (R-HSA-983168)
  Interleukin-7 signaling (R-HSA-1266695)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoinflammatory syndrome with immunodeficiency	DISPRSL8	Strong	Autosomal dominant	[1]
Autoimmune disease	DISORMTM	Limited	Autosomal dominant	[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 Suppressor of cytokine signaling 1 (SOCS1).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the methylation of Suppressor of cytokine signaling 1 (SOCS1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[14]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[17]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[5]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[8]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[5]
Bleomycin	DMNER5S	Approved	Bleomycin decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[8]
Lomustine	DMMWSUL	Approved	Lomustine decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[20]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[28]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Suppressor of cytokine signaling 1 (SOCS1).	[5]

References

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• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
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• [5] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
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• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [9] 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.
• [10] [Correlation of cell cycle alteration to SOCS-1 gene demethylation induced by arsenic trioxide in myeloma cell lines]. Ai Zheng. 2008 Nov;27(11):1150-4.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] DNA methylation regulates constitutive expression of Stat6 regulatory genes SOCS-1 and SHP-1 in colon cancer cells. J Cancer Res Clin Oncol. 2009 Dec;135(12):1791-8. doi: 10.1007/s00432-009-0627-z. Epub 2009 Jun 24.
• [13] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
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• [15] Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011 Aug 15;187(4):1778-87. doi: 10.4049/jimmunol.1003919. Epub 2011 Jul 18.
• [16] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
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• [18] Glucocorticoid regulation of human eosinophil gene expression. J Steroid Biochem Mol Biol. 2003 Mar;84(4):441-52. doi: 10.1016/s0960-0760(03)00065-7.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells. Phytomedicine. 2016 May 15;23(5):566-77. doi: 10.1016/j.phymed.2016.02.011. Epub 2016 Feb 27.
• [21] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [24] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.