Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5VYOSM)

• DOT Name: Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE)
• Synonyms: I-kappa-B kinase epsilon; IKK-E; IKK-epsilon; IkBKE; EC 2.7.11.10; Inducible I kappa-B kinase; IKK-i
• Gene Name: IKBKE
• Related Disease:
  Glioma
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Classic Hodgkin lymphoma
  Colorectal carcinoma
  Dengue
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Estrogen-receptor positive breast cancer
  Gastric cancer
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
  Influenza
  Kaposi sarcoma
  Major depressive disorder
  Malignant glioma
  Matthew-Wood syndrome
  Metabolic disorder
  Neuralgia
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic tumour
  Panic disorder
  Rheumatoid arthritis
  Sjogren syndrome
  Squamous cell carcinoma
  Stomach cancer
  Systemic lupus erythematosus
  Type-1/2 diabetes
  Breast neoplasm
  Chronic obstructive pulmonary disease
  Triple negative breast cancer
  Anxiety disorder
  Glioblastoma multiforme
  Non-small-cell lung cancer
  Obesity
  Psoriasis
• UniProt ID: IKKE_HUMAN
• EC Number: 2.7.11.10
• Pfam ID: PF00069 ; PF18394 ; PF18396
• Sequence:
  MQSTANYLWHTDDLLGQGATASVYKARNKKSGELVAVKVFNTTSYLRPREVQVREFEVLR
  KLNHQNIVKLFAVEETGGSRQKVLVMEYCSSGSLLSVLESPENAFGLPEDEFLVVLRCVV
  AGMNHLRENGIVHRDIKPGNIMRLVGEEGQSIYKLTDFGAARELDDDEKFVSVYGTEEYL
  HPDMYERAVLRKPQQKAFGVTVDLWSIGVTLYHAATGSLPFIPFGGPRRNKEIMYRITTE
  KPAGAIAGAQRRENGPLEWSYTLPITCQLSLGLQSQLVPILANILEVEQAKCWGFDQFFA
  ETSDILQRVVVHVFSLSQAVLHHIYIHAHNTIAIFQEAVHKQTSVAPRHQEYLFEGHLCV
  LEPSVSAQHIAHTTASSPLTLFSTAIPKGLAFRDPALDVPKFVPKVDLQADYNTAKGVLG
  AGYQALRLARALLDGQELMFRGLHWVMEVLQATCRRTLEVARTSLLYLSSSLGTERFSSV
  AGTPEIQELKAAAELRSRLRTLAEVLSRCSQNITETQESLSSLNRELVKSRDQVHEDRSI
  QQIQCCLDKMNFIYKQFKKSRMRPGLGYNEEQIHKLDKVNFSHLAKRLLQVFQEECVQKY
  QASLVTHGKRMRVVHETRNHLRLVGCSVAACNTEAQGVQESLSKLLEELSHQLLQDRAKG
  AQASPPPIAPYPSPTRKDLLLHMQELCEGMKLLASDLLDNNRIIERLNRVPAPPDV
• Function: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to viral infection, through the activation of the type I IFN, NF-kappa-B and STAT signaling. Also involved in TNFA and inflammatory cytokines, like Interleukin-1, signaling. Following activation of viral RNA sensors, such as RIG-I-like receptors, associates with DDX3X and phosphorylates interferon regulatory factors (IRFs), IRF3 and IRF7, as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRF3 leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNB. In order to establish such an antiviral state, IKBKE forms several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including IPS1/MAVS, TANK, AZI2/NAP1 or TBKBP1/SINTBAD can be recruited to the IKBKE-containing-complexes. Activated by polyubiquitination in response to TNFA and interleukin-1, regulates the NF-kappa-B signaling pathway through, at least, the phosphorylation of CYLD. Phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. In addition, is also required for the induction of a subset of ISGs which displays antiviral activity, may be through the phosphorylation of STAT1 at 'Ser-708'. Phosphorylation of STAT1 at 'Ser-708' seems also to promote the assembly and DNA binding of ISGF3 (STAT1:STAT2:IRF9) complexes compared to GAF (STAT1:STAT1) complexes, in this way regulating the balance between type I and type II IFN responses. Protects cells against DNA damage-induced cell death. Also plays an important role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Phosphorylates AKT1.
• Tissue Specificity: Highly expressed in spleen followed by thymus, peripheral blood leukocytes, pancreas, placenta. Weakly expressed in lung, kidney, prostate, ovary and colon.
• KEGG Pathway:
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  C-type lectin receptor sig.ling pathway (hsa04625)
  IL-17 sig.ling pathway (hsa04657)
  Alcoholic liver disease (hsa04936)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TICAM1-dependent activation of IRF3/IRF7 (R-HSA-9013973)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Activation of IRF3, IRF7 mediated by TBK1, IKK (IKBKE) (R-HSA-936964)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  SUMOylation of immune response proteins (R-HSA-4755510)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Posttranslational Modification	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Dengue	DISKH221	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[10]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[11]
Gastric cancer	DISXGOUK	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[14]
Influenza	DIS3PNU3	Strong	Biomarker	[15]
Kaposi sarcoma	DISC1H1Z	Strong	Biomarker	[16]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[17]
Malignant glioma	DISFXKOV	Strong	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[18]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Neuralgia	DISWO58J	Strong	Biomarker	[19]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[20]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[9]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[9]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[18]
Panic disorder	DISD3VNY	Strong	Biomarker	[17]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[21]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[23]
Stomach cancer	DISKIJSX	Strong	Biomarker	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[24]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[25]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[26]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[27]
Triple negative breast cancer	DISAMG6N	moderate	Biomarker	[28]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[29]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[30]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[31]
Obesity	DIS47Y1K	Limited	Altered Expression	[32]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[33]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) affects the response to substance of Daunorubicin.	[52]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[36]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[38]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[39]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[39]
Marinol	DM70IK5	Approved	Marinol increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[40]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[41]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[42]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[43]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[43]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[44]
Amlexanox	DM0DQM5	Approved	Amlexanox decreases the activity of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[45]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[46]
Tempol	DMUQH78	Phase 2	Tempol decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[47]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[49]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[50]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[51]
BX-795	DMRIMLJ	Investigative	BX-795 decreases the activity of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[45]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE).	[48]

References

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