Target Information

Target General Information

Target ID

T40192 (Former ID: TTDI01966)

Target 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

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Gene Name

NFKB1

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Muscular dystrophy [ICD-11: 8C70]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Type 2 diabetes mellitus [ICD-11: 5A11]

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.

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UniProt ID

NFKB1_HUMAN

Sequence

MAEDDPYLGRPEQMFHLDPSLTHTIFNPEVFQPQMALPTDGPYLQILEQPKQRGFRFRYV
CEGPSHGGLPGASSEKNKKSYPQVKICNYVGPAKVIVQLVTNGKNIHLHAHSLVGKHCED
GICTVTAGPKDMVVGFANLGILHVTKKKVFETLEARMTEACIRGYNPGLLVHPDLAYLQA
EGGGDRQLGDREKELIRQAALQQTKEMDLSVVRLMFTAFLPDSTGSFTRRLEPVVSDAIY
DSKAPNASNLKIVRMDRTAGCVTGGEEIYLLCDKVQKDDIQIRFYEEEENGGVWEGFGDF
SPTDVHRQFAIVFKTPKYKDINITKPASVFVQLRRKSDLETSEPKPFLYYPEIKDKEEVQ
RKRQKLMPNFSDSFGGGSGAGAGGGGMFGSGGGGGGTGSTGPGYSFPHYGFPTYGGITFH
PGTTKSNAGMKHGTMDTESKKDPEGCDKSDDKNTVNLFGKVIETTEQDQEPSEATVGNGE
VTLTYATGTKEESAGVQDNLFLEKAMQLAKRHANALFDYAVTGDVKMLLAVQRHLTAVQD
ENGDSVLHLAIIHLHSQLVRDLLEVTSGLISDDIINMRNDLYQTPLHLAVITKQEDVVED
LLRAGADLSLLDRLGNSVLHLAAKEGHDKVLSILLKHKKAALLLDHPNGDGLNAIHLAMM
SNSLPCLLLLVAAGADVNAQEQKSGRTALHLAVEHDNISLAGCLLLEGDAHVDSTTYDGT
TPLHIAAGRGSTRLAALLKAAGADPLVENFEPLYDLDDSWENAGEDEGVVPGTTPLDMAT
SWQVFDILNGKPYEPEFTSDDLLAQGDMKQLAEDVKLQLYKLLEIPDPDKNWATLAQKLG
LGILNNAFRLSPAPSKTLMDNYEVSGGTVRELVEALRQMGYTEAIEVIQAASSPVKTTSQ
AHSLPLSPASTRQQIDELRDSDSVCDSGVETSFRKLSFTESLTSGASLLTLNKMPHDYGQ
EGPLEGKI

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3D Structure

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AlphaFold

ADReCS ID

BADD_A03065 ; BADD_A03470 ; BADD_A05675

HIT2.0 ID

T06RMZ

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

CAT 1004

Drug Info

Phase 2

Duchenne dystrophy

[3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

CAT 1004

Drug Info

[4]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Ankyrin repeat domain-containing protein 62 (ANKRD62)	PF13606 ; PF13857 ; PF14915 More >>	30.968 (48/155)	1.16E-07
Protein phosphatase 1 regulatory subunit 27 (PPP1R27)	PF13637	35.135 (39/111)	2.15E-07
CDK inhibitor 4C p18-INK4c (CDKN2C)	PF13637	37.931 (33/87)	4.50E-05
DNA-binding protein RFXANK (RFXANK)	PF13606 ; PF13857	30.328 (37/122)	1.01E-04


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Ras signaling pathway	hsa04014	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cAMP signaling pathway	hsa04024	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Chemokine signaling pathway	hsa04062	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
NF-kappa B signaling pathway	hsa04064	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
HIF-1 signaling pathway	hsa04066	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Sphingolipid signaling pathway	hsa04071	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Apoptosis	hsa04210	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Longevity regulating pathway	hsa04211	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Cellular senescence	hsa04218	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Osteoclast differentiation	hsa04380	Affiliated Target
Class: Organismal Systems => Development and regeneration	Pathway Hierarchy
Neutrophil extracellular trap formation	hsa04613	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Toll-like receptor signaling pathway	hsa04620	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
NOD-like receptor signaling pathway	hsa04621	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
RIG-I-like receptor signaling pathway	hsa04622	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Cytosolic DNA-sensing pathway	hsa04623	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
C-type lectin receptor signaling pathway	hsa04625	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
IL-17 signaling pathway	hsa04657	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th1 and Th2 cell differentiation	hsa04658	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th17 cell differentiation	hsa04659	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
B cell receptor signaling pathway	hsa04662	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
TNF signaling pathway	hsa04668	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neurotrophin signaling pathway	hsa04722	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Prolactin signaling pathway	hsa04917	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Adipocytokine signaling pathway	hsa04920	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Relaxin signaling pathway	hsa04926	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	33	Degree centrality	3.55E-03	Betweenness centrality	8.28E-04
Closeness centrality	2.54E-01	Radiality	1.44E+01	Clustering coefficient	2.67E-01
Neighborhood connectivity	5.30E+01	Topological coefficient	6.73E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 49 KEGG Pathways	+
1	MAPK signaling pathway
2	Ras signaling pathway
3	cAMP signaling pathway
4	Chemokine signaling pathway
5	NF-kappa B signaling pathway
6	HIF-1 signaling pathway
7	Sphingolipid signaling pathway
8	PI3K-Akt signaling pathway
9	Apoptosis
10	Osteoclast differentiation
11	Toll-like receptor signaling pathway
12	NOD-like receptor signaling pathway
13	RIG-I-like receptor signaling pathway
14	Cytosolic DNA-sensing pathway
15	T cell receptor signaling pathway
16	B cell receptor signaling pathway
17	TNF signaling pathway
18	Neurotrophin signaling pathway
19	Prolactin signaling pathway
20	Adipocytokine signaling pathway
21	Non-alcoholic fatty liver disease (NAFLD)
22	Cocaine addiction
23	Epithelial cell signaling in Helicobacter pylori infection
24	Shigellosis
25	Salmonella infection
26	Pertussis
27	Legionellosis
28	Leishmaniasis
29	Chagas disease (American trypanosomiasis)
30	Toxoplasmosis
31	Amoebiasis
32	Tuberculosis
33	Hepatitis C
34	Hepatitis B
35	Measles
36	Influenza A
37	HTLV-I infection
38	Herpes simplex infection
39	Epstein-Barr virus infection
40	Pathways in cancer
41	Transcriptional misregulation in cancer
42	Viral carcinogenesis
43	MicroRNAs in cancer
44	Pancreatic cancer
45	Prostate cancer
46	Chronic myeloid leukemia
47	Acute myeloid leukemia
48	Small cell lung cancer
49	Inflammatory bowel disease (IBD)
NetPath Pathway	[+] 6 NetPath Pathways	+
1	IL5 Signaling Pathway
2	IL1 Signaling Pathway
3	TCR Signaling Pathway
4	IL2 Signaling Pathway
5	TNFalpha Signaling Pathway
6	Leptin Signaling Pathway
Panther Pathway	[+] 2 Panther Pathways	+
1	Apoptosis signaling pathway
2	T cell activation
Pathwhiz Pathway	[+] 2 Pathwhiz Pathways	+
1	Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
2	Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
PID Pathway	[+] 21 PID Pathways	+
1	Fc-epsilon receptor I signaling in mast cells
2	BCR signaling pathway
3	LPA receptor mediated events
4	Atypical NF-kappaB pathway
5	Canonical NF-kappaB pathway
6	CD40/CD40L signaling
7	IL12-mediated signaling events
8	Alternative NF-kappaB pathway
9	Osteopontin-mediated events
10	Angiopoietin receptor Tie2-mediated signaling
11	Signaling events mediated by HDAC Class I
12	Regulation of Telomerase
13	IL1-mediated signaling events
14	Glucocorticoid receptor regulatory network
15	TNF receptor signaling pathway
16	IL2 signaling events mediated by PI3K
17	Ceramide signaling pathway
18	amb2 Integrin signaling
19	IL23-mediated signaling events
20	HIV-1 Nef: Negative effector of Fas and TNF-alpha
21	EPO signaling pathway
Reactome	[+] 17 Reactome Pathways	+
1	Activation of NF-kappaB in B cells
2	RIP-mediated NFkB activation via ZBP1
3	Regulated proteolysis of p75NTR
4	NF-kB is activated and signals survival
5	Senescence-Associated Secretory Phenotype (SASP)
6	FCERI mediated NF-kB activation
7	DEx/H-box helicases activate type I IFN and inflammatory cytokines production
8	Transcriptional regulation of white adipocyte differentiation
9	TAK1 activates NFkB by phosphorylation and activation of IKKs complex
10	Interleukin-1 processing
11	IKBKG deficiency causes anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (via TLR)
12	IkBA variant leads to EDA-ID
13	CLEC7A (Dectin-1) signaling
14	CD209 (DC-SIGN) signaling
15	CLEC7A/inflammasome pathway
16	MAP3K8 (TPL2)-dependent MAPK1/3 activation
17	TRAF6 mediated NF-kB activation
WikiPathways	[+] 57 WikiPathways	+
1	Toll-like receptor signaling pathway
2	DNA Damage Response (only ATM dependent)
3	SIDS Susceptibility Pathways
4	TCR Signaling Pathway
5	Notch Signaling Pathway
6	TGF Beta Signaling Pathway
7	Oxidative Stress
8	IL-4 Signaling Pathway
9	Apoptosis Modulation by HSP70
10	MAPK Signaling Pathway
11	Myometrial Relaxation and Contraction Pathways
12	IL1 and megakaryotyces in obesity
13	Apoptosis-related network due to altered Notch3 in ovarian cancer
14	Hair Follicle Development: Cytodifferentiation (Part 3 of 3)
15	Hair Follicle Development: Organogenesis (Part 2 of 3)
16	Hair Follicle Development: Induction (Part 1 of 3)
17	Selenium Metabolism and Selenoproteins
18	Cardiac Hypertrophic Response
19	Cytosolic sensors of pathogen-associated DNA
20	Fc epsilon receptor (FCERI) signaling
21	Transcriptional Regulation of White Adipocyte Differentiation
22	Signaling by the B Cell Receptor (BCR)
23	TAK1 activates NFkB by phosphorylation and activation of IKKs complex
24	Structural Pathway of Interleukin 1 (IL-1)
25	EBV LMP1 signaling
26	Aryl Hydrocarbon Receptor
27	T-Cell Receptor and Co-stimulatory Signaling
28	Apoptosis
29	Quercetin and Nf-kB/ AP-1 Induced Cell Apoptosis
30	BDNF signaling pathway
31	Integrated Pancreatic Cancer Pathway
32	Oncostatin M Signaling Pathway
33	Corticotropin-releasing hormone
34	AGE/RAGE pathway
35	TNF alpha Signaling Pathway
36	B Cell Receptor Signaling Pathway
37	TSLP Signaling Pathway
38	IL17 signaling pathway
39	Neural Crest Differentiation
40	TWEAK Signaling Pathway
41	Leptin signaling pathway
42	RANKL/RANK Signaling Pathway
43	Integrated Breast Cancer Pathway
44	Signalling by NGF
45	IL-1 signaling pathway
46	TCR signaling
47	RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways
48	Interleukin-1 signaling
49	Interleukin-1 processing
50	Apoptosis Modulation and Signaling
51	Folate Metabolism
52	TFs Regulate miRNAs related to cardiac hypertrophy
53	MicroRNAs in cardiomyocyte hypertrophy
54	Vitamin B12 Metabolism
55	Selenium Micronutrient Network
56	Regulation of toll-like receptor signaling pathway
57	Osteopontin Signaling

References

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REF 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.

REF 2

Biotechnology in Comparative Perspective, Gerhard Fuchs. Page(82).

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

Clinical pipeline report, company report or official report of Catabasis Pharmaceuticals Inc.

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