Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS231V7)

• DOT Name: Nuclear factor NF-kappa-B p100 subunit (NFKB2)
• Synonyms: DNA-binding factor KBF2; H2TF1; Lymphocyte translocation chromosome 10 protein; Nuclear factor of kappa light polypeptide gene enhancer in B-cells 2; Oncogene Lyt-10; Lyt10
• Gene Name: NFKB2
• Related Disease:
  Immunodeficiency, common variable, 10
  Common variable immunodeficiency
  Deficiency in anterior pituitary function - variable immunodeficiency syndrome
• UniProt ID: NFKB2_HUMAN
• PDB ID: 1A3Q; 2D96; 3DO7; 4OT9; 5ZMC; 7CLI; 7VUP; 7VUQ; 7W7L
• Pfam ID: PF12796 ; PF00531 ; PF16179 ; PF00554
• Sequence:
  MESCYNPGLDGIIEYDDFKLNSSIVEPKEPAPETADGPYLVIVEQPKQRGFRFRYGCEGP
  SHGGLPGASSEKGRKTYPTVKICNYEGPAKIEVDLVTHSDPPRAHAHSLVGKQCSELGIC
  AVSVGPKDMTAQFNNLGVLHVTKKNMMGTMIQKLQRQRLRSRPQGLTEAEQRELEQEAKE
  LKKVMDLSIVRLRFSAFLRASDGSFSLPLKPVISQPIHDSKSPGASNLKISRMDKTAGSV
  RGGDEVYLLCDKVQKDDIEVRFYEDDENGWQAFGDFSPTDVHKQYAIVFRTPPYHKMKIE
  RPVTVFLQLKRKRGGDVSDSKQFTYYPLVEDKEEVQRKRRKALPTFSQPFGGGSHMGGGS
  GGAAGGYGGAGGGGSLGFFPSSLAYSPYQSGAGPMGCYPGGGGGAQMAATVPSRDSGEEA
  AEPSAPSRTPQCEPQAPEMLQRAREYNARLFGLAQRSARALLDYGVTADARALLAGQRHL
  LTAQDENGDTPLHLAIIHGQTSVIEQIVYVIHHAQDLGVVNLTNHLHQTPLHLAVITGQT
  SVVSFLLRVGADPALLDRHGDSAMHLALRAGAGAPELLRALLQSGAPAVPQLLHMPDFEG
  LYPVHLAVRARSPECLDLLVDSGAEVEATERQGGRTALHLATEMEELGLVTHLVTKLRAN
  VNARTFAGNTPLHLAAGLGYPTLTRLLLKAGADIHAENEEPLCPLPSPPTSDSDSDSEGP
  EKDTRSSFRGHTPLDLTCSTKVKTLLLNAAQNTMEPPLTPPSPAGPGLSLGDTALQNLEQ
  LLDGPEAQGSWAELAERLGLRSLVDTYRQTTSPSGSLLRSYELAGGDLAGLLEALSDMGL
  EEGVRLLRGPETRDKLPSTAEVKEDSAYGSQSVEQEAEKLGPPPEPPGGLCHGHPQPQVH
• Function: NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. In a non-canonical activation pathway, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. The NF-kappa-B heterodimeric RelB-p52 complex is a transcriptional activator. The NF-kappa-B p52-p52 homodimer is a transcriptional repressor. NFKB2 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p100 and generation of p52 by a cotranslational processing. The proteasome-mediated process ensures the production of both p52 and p100 and preserves their independent function. p52 binds to the kappa-B consensus sequence 5'-GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. p52 and p100 are respectively the minor and major form; the processing of p100 being relatively poor. Isoform p49 is a subunit of the NF-kappa-B protein complex, which stimulates the HIV enhancer in synergy with p65. In concert with RELB, regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Legionellosis (hsa05134)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Breast cancer (hsa05224)
• Reactome Pathway:
  DEx/H-box helicases activate type I IFN and inflammatory cytokines production (R-HSA-3134963)
  PKMTs methylate histone lysines (R-HSA-3214841)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  Interleukin-1 processing (R-HSA-448706)
  SUMOylation of immune response proteins (R-HSA-4755510)
  IkBA variant leads to EDA-ID (R-HSA-5603029)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  The NLRP3 inflammasome (R-HSA-844456)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  Purinergic signaling in leishmaniasis infection (R-HSA-9660826)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency, common variable, 10	DISGAOEI	Definitive	Autosomal dominant	[1]
Common variable immunodeficiency	DISHE7JQ	Supportive	Autosomal dominant	[2]
Deficiency in anterior pituitary function - variable immunodeficiency syndrome	DISWWXOJ	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Nuclear factor NF-kappa-B p100 subunit (NFKB2) affects the response to substance of Doxorubicin.	[35]

2 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 Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[16]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[17]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[18]
Gemcitabine	DMSE3I7	Approved	Gemcitabine affects the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[19]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[20]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[21]
Omacetaxine mepesuccinate	DMPU2WX	Approved	Omacetaxine mepesuccinate increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[23]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the activity of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[29]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[30]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[31]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[32]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[33]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[23]
BAY11-7082	DMQNOFA	Investigative	BAY11-7082 decreases the activity of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[24]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
NMS-873	DMYKZ6U	Investigative	NMS-873 decreases the metabolism of Nuclear factor NF-kappa-B p100 subunit (NFKB2).	[34]

References

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