Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Nuclear factor NF-kappa-B (NFKB)
• Synonyms: Nuclear factor of kappa light polypeptide gene enhancer in B-cells; DNA-binding factor KBF
• Gene Name: NFKB1; NFKB2; RELA; RELB; REL
• DTT Type: Successful target; [1]
• Related Disease:
  Irritable bowel syndrome [ICD-11: DD91]
  Rheumatoid arthritis [ICD-11: FA20]
• UniProt ID: NFKB1_HUMAN ; NFKB2_HUMAN ; TF65_HUMAN ; RELB_HUMAN ; REL_HUMAN
• TTD ID: T83145
• 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. 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-ARNTL/BMAL1 heterodimer. 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)
  NF-kappa B signaling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Legionellosis (hsa05134)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  DEx/H-box helicases activate type I IFN and inflammatory cytokines production (R-HSA-3134963)
  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)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Sulfasalazine	DMICA9H	Irritable bowel syndrome	DD91.0	Approved	[1]

14 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Edasalonexent	DMYVBF6	Duchenne dystrophy	8C70	Phase 3	[2]
Laquinimod	DM3IWS8	Lupus	4A40	Phase 3	[3]
MD1003	DMVZ57G	Multiple sclerosis	8A40	Phase 3	[2]
Triptolide	DMCMDVR	Autoimmune diabetes	5A10	Phase 3	[4]
CAT 1004	DMQBP7R	Duchenne dystrophy	8C70	Phase 2	[5]
CZEN-002	DMUDMHA	Fungal infection	1F29-1F2F	Phase 2	[6]
L-ornithine phenylacetate	DM0GZTD	Acute liver failure	DB91	Phase 2	[7]
Parthenolide	DMCQBFT	N. A.	N. A.	Phase 2	[8]
PRO22	DMMEL6B	Atopic dermatitis	EA80	Phase 2	[9]
Recoflavone	DMCSR8I	Inflammatory bowel disease	DD72	Phase 2	[10]
Vadimezan	DMK7CYX	Solid tumour/cancer	2A00-2F9Z	Phase 2	[11]
XP-23829	DMELUYN	Multiple sclerosis	8A40	Phase 2	[12]
Avrina	DMRS58M	Skin infection	1F28-1G0Z	Phase 1/2	[7]
LC-1	DMJEACT	Acute myeloid leukaemia	2A60	Phase 1	[13]

41 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 1	DMK75BT	Muscular wasting	8C7Y	Patented	[14]
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 2	DMIWQZ5	Muscular wasting	8C7Y	Patented	[14]
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 3	DMNXAUZ	Muscular wasting	8C7Y	Patented	[14]
1-hydroxyl-3,5-bis(4-hydroxylstyryl)benzene derivative 4	DMV2W9Z	Muscular wasting	8C7Y	Patented	[14]
N-quinolin-benzene sulphonamide derivative 1	DMLSK97	N. A.	N. A.	Patented	[14]
N-quinolin-benzene sulphonamide derivative 2	DMH65CX	N. A.	N. A.	Patented	[14]
N-quinolin-benzene sulphonamide derivative 3	DMU65YX	N. A.	N. A.	Patented	[14]
Olenolic acid acetate derivative 1	DMZIALN	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-EP20132578214 2	DM4GQJH	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-US2011000295210	DMM3QEW	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2011788838110	DMZCO6J	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2011796857710	DMH4DMY	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2011799419010	DMIZ64O	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2011801300410	DMZ96CG	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2011803494010	DMCDHZT	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2011806744710	DMIAV5M	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2012810604610	DM9KAF1	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2012819831110	DMS7RYP	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2012820715110	DMDQ6H7	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2012830453910	DMCUMSV	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US2012832440110	DMFCE51	Immune System disease	4A01-4B41	Patented	[14]
PMID25553724-Compound-US20130116324 2	DMUBZO3	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-US20138552206 4	DMV7SQH	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-US20138552206 5	DMRVE7Z	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2011127048 31	DM5ATIV	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2011127048 32	DMH3NOZ	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2011127048 33	DMH7496	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2011127048 34	DM4YE8W	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2011152671 2	DMPQ175	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2013082253 31	DMPFMSJ	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2013082253 32	DMXYSO1	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2013082253 33	DMR1YH9	N. A.	N. A.	Patented	[14]
PMID25553724-Compound-WO2013082253 34	DML1U69	N. A.	N. A.	Patented	[14]
Quinoxaline derivative 1	DMENQ5O	N. A.	N. A.	Patented	[14]
Quinoxaline derivative 2	DM031YW	N. A.	N. A.	Patented	[14]
Quinoxaline derivative 3	DMLZRAI	N. A.	N. A.	Patented	[14]
Quinoxaline derivative 4	DMS3PRT	N. A.	N. A.	Patented	[14]
Quinoxaline derivative 5	DM8EY2G	N. A.	N. A.	Patented	[14]
Quinoxaline derivative 6	DMBRX8D	N. A.	N. A.	Patented	[14]
Tihotungstate derivative 1	DM5UI73	Aberrant vascularization	BE2Z	Patented	[14]
Tihourea derivative 1	DMGR6IJ	N. A.	N. A.	Patented	[14]

7 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
P-1	DMFNLDY	Atopic dermatitis	EA80	Discontinued in Phase 3	[15]
AS602868	DMKXDOI	Multiple myeloma	2A83	Discontinued in Phase 1	[16]
SIM-916	DMTGCSX	Gynecological disease	GA6Z	Discontinued in Phase 1	[7]
Gliotoxin	DMONQYZ	N. A.	N. A.	Terminated	[17]
HELENALIN	DMMCI4H	N. A.	N. A.	Terminated	[18]
MOL-218	DM543VY	Asthma	CA23	Terminated	[19]
Tyloxapol	DMR3S9B	Cystic fibrosis	CA25	Terminated	[20], [21]

50 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
15-ACETOXY-EREMANTHOLIDE B	DMLSZW2	Discovery agent	N.A.	Investigative	[18]
15-DEOXYBUDLEIN A	DMJC0NQ	Discovery agent	N.A.	Investigative	[18]
15-deoxygoiazensolide	DMR9SFM	Discovery agent	N.A.	Investigative	[22]
15-isobutyrylmiguanin	DMQCRUG	Discovery agent	N.A.	Investigative	[22]
1beta-methoxy-miller-9Z-enolide	DMHR90S	Discovery agent	N.A.	Investigative	[22]
2-amino-N-(quinolin-8-yl)benzenesulfonamide	DMESFTW	Discovery agent	N.A.	Investigative	[23]
2-nitro-N-(quinolin-8-yl)benzenesulfonamide	DM4Z56O	Discovery agent	N.A.	Investigative	[23]
2-oxoguaia-1,4(15), 11(13)-trien-12,8beta-olide	DM3UY74	Discovery agent	N.A.	Investigative	[22]
2-oxoguaia-1,4,11(13)-trien-12,8alpha-olide	DM23WOV	Discovery agent	N.A.	Investigative	[22]
2beta-methoxy-2-deethoxyphantomolin	DMWZ4KN	Discovery agent	N.A.	Investigative	[22]
3,4-epoxydehydroleucodin	DM8BJPU	Discovery agent	N.A.	Investigative	[22]
4,5-ISOBUDLEIN A	DMXNP2W	Discovery agent	N.A.	Investigative	[22]
4-nitro-N-(quinolin-8-yl)benzenesulfonamide	DMLJDU5	Discovery agent	N.A.	Investigative	[23]
4beta,15-epoxy-miller-9E-enolide	DMDF3KJ	Discovery agent	N.A.	Investigative	[22]
4beta,15-epoxy-miller-9Z-enolide	DMZ01SV	Discovery agent	N.A.	Investigative	[22]
5-bromo-N-(quinolin-8-yl)thiophene-2-sulfonamide	DM37T5L	Discovery agent	N.A.	Investigative	[23]
5-chloro-N-(quinolin-8-yl)thiophene-2-sulfonamide	DMMV931	Discovery agent	N.A.	Investigative	[23]
5H-6-thia-4,5-diaza-chrysene 6,6-dioxide	DM1SON5	Discovery agent	N.A.	Investigative	[23]
7-hydroxycostunolide	DMV0PT8	Discovery agent	N.A.	Investigative	[22]
9-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide	DMK5DUA	Discovery agent	N.A.	Investigative	[23]
9-fluoro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide	DMLK0TX	Discovery agent	N.A.	Investigative	[23]
9-methyl-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide	DMKD0ZP	Discovery agent	N.A.	Investigative	[23]
9alpha-acetoxy-miller-1(10)Z-enolide	DMO9R6T	Discovery agent	N.A.	Investigative	[22]
ACHP	DMZO5Y7	Multiple myeloma	2A83	Investigative	[16]
ARTOBILOXANTHONE	DMB9AR7	Discovery agent	N.A.	Investigative	[24]
ARTORIGIDIN A	DMHUXRP	Discovery agent	N.A.	Investigative	[24]
ATRIPLICIOLIDTIGLATE	DML2MAI	Discovery agent	N.A.	Investigative	[18]
BAY11-7082	DMQNOFA	Multiple myeloma	2A83	Investigative	[16]
BUDLEIN A	DMQVL2U	Discovery agent	N.A.	Investigative	[18]
Caffeic acid phenethyl ester	DMRJKIV	Discovery agent	N.A.	Investigative	[25]
Centratherin	DMOHELX	Discovery agent	N.A.	Investigative	[22]
DTD	DMPKTB4	Discovery agent	N.A.	Investigative	[26]
ENHYDRIN	DM0STFR	Discovery agent	N.A.	Investigative	[22]
G6976	DMEZO4M	Solid tumour/cancer	2A00-2F9Z	Investigative	[27]
Helenalin-2-methylbutyrate	DMQPCDG	Discovery agent	N.A.	Investigative	[22]
HELENALINMETHACRYLATE	DMPOALD	Discovery agent	N.A.	Investigative	[22]
IkappaB-alphaM	DM2X3EV	Discovery agent	N.A.	Investigative	[28]
ISOGOIAZENSOLIDE	DMCF1ZD	Discovery agent	N.A.	Investigative	[18]
Isohelenin	DMZH9PW	Discovery agent	N.A.	Investigative	[29]
Miller-9E-enolide	DM6BANS	Discovery agent	N.A.	Investigative	[22]
Miller-9Z-enolide	DMFMOX5	Discovery agent	N.A.	Investigative	[22]
MOLEPHANTIN	DM4OLAZ	Discovery agent	N.A.	Investigative	[18]
MOLEPHANTININ	DMGNX6M	Discovery agent	N.A.	Investigative	[18]
N-(quinolin-8-yl)thiophene-2-sulfonamide	DM7O1F3	Discovery agent	N.A.	Investigative	[23]
PS-1145	DMVUMWZ	Multiple myeloma	2A83	Investigative	[16]
Pycnogenol	DMLFJHE	Discovery agent	N.A.	Investigative	[30]
Pyrrolidine dithiocarbamate	DM5ZAS6	Discovery agent	N.A.	Investigative	[31], [32]
ROCAGLAMIDE	DME9VTX	Discovery agent	N.A.	Investigative	[24]
SCANDENOLIDE	DMX40NM	Discovery agent	N.A.	Investigative	[18]
SP-650003	DM4SXIT	Discovery agent	N.A.	Investigative	[33]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	7.34E-09	0.84	3.94
Acute myelocytic leukaemia	2C82	Bone marrow	5.39E-01	0.16	0.27
Atopic dermatitis	EA90	Skin	7.38E-10	0.54	2.85
Asthma	CA23	Nasal and bronchial airway	7.89E-02	-0.2	-0.39
Multiple myeloma	2C82	Bone marrow	7.23E-01	0.02	0.08
Liver failure	DD91.0	Liver tissue	3.14E-01	0.22	0.64

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