Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5O11J0)

• DOT Name: Suppressor of IKBKE 1 (SIKE1)
• Synonyms: Suppressor of IKK-epsilon
• Gene Name: SIKE1
• Related Disease: Cryohydrocytosis
• UniProt ID: SIKE1_HUMAN
• PDB ID: 6AKK; 6AKL; 6AKM
• Pfam ID: PF05769
• Sequence:
  MSCTIEKILTDAKTLLERLREHDAAAESLVDQSAALHRRVAAMREAGTALPDQYQEDASD
  MKDMSKYKPHILLSQENTQIRDLQQENRELWISLEEHQDALELIMSKYRKQMLQLMVAKK
  AVDAEPVLKAHQSHSAEIESQIDRICEMGEVMRKAVQVDDDQFCKIQEKLAQLELENKEL
  RELLSISSESLQARKENSMDTASQAIK
• Function: Physiological suppressor of IKK-epsilon and TBK1 that plays an inhibitory role in virus- and TLR3-triggered IRF3. Inhibits TLR3-mediated activation of interferon-stimulated response elements (ISRE) and the IFN-beta promoter. May act by disrupting the interactions of IKBKE or TBK1 with TICAM1/TRIF, IRF3 and RIGI. Does not inhibit NF-kappa-B activation pathways.
• Tissue Specificity: Widely expressed. Expressed in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and leukocytes. Present in all cell lines tested (at protein level).
• KEGG Pathway: RIG-I-like receptor sig.ling pathway (hsa04622)
• Reactome Pathway:
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cryohydrocytosis	DISMQHL3	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Suppressor of IKBKE 1 (SIKE1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Suppressor of IKBKE 1 (SIKE1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Suppressor of IKBKE 1 (SIKE1).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Suppressor of IKBKE 1 (SIKE1).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Suppressor of IKBKE 1 (SIKE1).	[6]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Suppressor of IKBKE 1 (SIKE1).	[7]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Suppressor of IKBKE 1 (SIKE1).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Suppressor of IKBKE 1 (SIKE1).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Suppressor of IKBKE 1 (SIKE1).	[10]

References

• [1] Peripheral B cells may serve as a reservoir for persistent hepatitis C virus infection.J Innate Immun. 2010;2(6):607-17. doi: 10.1159/000317690. Epub 2010 Aug 17.
• [2] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [8] 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.
• [9] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.