Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUIZKC)

• DTT Name: DNA-binding factor KBF1 (p105)
• Synonyms: Nuclear factor of kappa light polypeptide gene enhancer in Bcells 1; Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; Nuclear factor NFkappaB p50 subunit; Nuclear factor NFkappaB p105 subunit; Nuclear factor NF-kappa-B p105 subunit; EBP1; EBP-1; DNAbinding factor KBF1
• Gene Name: NFKB1
• DTT Type: Clinical trial target; [1]
• UniProt ID: NFKB1_HUMAN
• TTD ID: T40192
• Sequence:
  MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYV
  CEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCED
  GICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQA
  EGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIY
  DSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDF
  SPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQ
  RKRQKLMPNFSDSFGGGSGAGAGGGGMFGSGGGGGGTGSTGPGYSFPHYGFPTYGGITFH
  PGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGE
  VTLTYATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQD
  ENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVED
  LLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMM
  SNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGT
  TPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMAT
  SWQVFDILNGKPYEPEFTSDDLLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLG
  LGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQ
  AHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQ
  EGPLEGKI
• Function: 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 and the heterodimeric p65-p50 complex appears to be most abundant one. 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. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post-translationally. p50 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. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105. 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.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Ras signaling pathway (hsa04014)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  NF-kappa B signaling pathway (hsa04064)
  HIF-1 signaling pathway (hsa04066)
  Sphingolipid signaling pathway (hsa04071)
  PI3K-Akt signaling pathway (hsa04151)
  Apoptosis (hsa04210)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  Cytosolic DNA-sensing pathway (hsa04623)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  TNF signaling pathway (hsa04668)
  Neurotrophin signaling pathway (hsa04722)
  Prolactin signaling pathway (hsa04917)
  Adipocytokine signaling pathway (hsa04920)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Cocaine addiction (hsa05030)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Leishmaniasis (hsa05140)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
  MicroRNAs in cancer (hsa05206)
  Pancreatic cancer (hsa05212)
  Prostate cancer (hsa05215)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Small cell lung cancer (hsa05222)
  Inflammatory bowel disease (IBD) (hsa05321)
• Reactome Pathway:
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NF-kB is activated and signals survival (R-HSA-209560)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  DEx/H-box helicases activate type I IFN and inflammatory cytokines production (R-HSA-3134963)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  TAK1 activates NFkB by phosphorylation and activation of IKKs complex (R-HSA-445989)
  Interleukin-1 processing (R-HSA-448706)
  IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR) (R-HSA-5603027)
  IkBA variant leads to EDA-ID (R-HSA-5603029)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  CLEC7A/inflammasome pathway (R-HSA-5660668)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CAT 1004	DMQBP7R	Duchenne dystrophy	8C70	Phase 2	[2]
P54	DMCBEYH	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	6.21E-01	0.02	0.09

References

• [1] Identification of p54(nrb) and the 14-3-3 Protein HS1 as TNF-alpha-inducible genes related to cell cycle control and apoptosis in human arterial endothelial cells. J Biochem Mol Biol. 2005 Jul 31;38(4):447-56.
• [2] Clinical pipeline report, company report or official report of Catabasis Pharmaceuticals Inc.