mitogen-activated protein kinase kinase kinase 14 | STE-unique family | IUPHAR/BPS Guide to PHARMACOLOGY

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mitogen-activated protein kinase kinase kinase 14

target has curated data in GtoImmuPdb

Target id: 2074

Nomenclature: mitogen-activated protein kinase kinase kinase 14

Abbreviated Name: NIK

Family: STE-unique family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 947 17q21-q22 MAP3K14 mitogen-activated protein kinase kinase kinase 14
Mouse - 942 11 E1 Map3k14 mitogen-activated protein kinase kinase kinase 14
Rat - 942 10 q32.1 Map3k14 mitogen-activated protein kinase kinase kinase 14
Previous and Unofficial Names
NF-κB-inducing kinase | NIK
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human NF-kappaB inducing kinase (NIK)
PDB Id:  4G3D
Resolution:  2.9Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of NIK with compound 4-{3-[2-amino-5-(2-methoxyethoxy)pyrimidin-4-yl]-1H-indol-5-yl}-2-methylbut-3-yn-2-ol (13V).
PDB Id:  4IDV
Ligand:  compound 31 [PMID: 23374866]
Resolution:  2.9Å
Species:  Human
References:  4
Enzyme Reaction
EC Number: 2.7.11.25

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
NIK SMI1 Hs Inhibition 9.6 pKi 2
pKi 9.6 (Ki 2.3x10-10 M) [2]
NIK SMI1 Mm Inhibition 9.4 pKi 2
pKi 9.4 (Ki 3.95x10-10 M) [2]
compound 31 [PMID: 23374866] Hs Inhibition 7.7 pIC50 4
pIC50 7.7 (IC50 2x10-8 M) [4]
compound 3a [Pipionne et al, 2018] Hs Inhibition 5.1 pIC50 5
pIC50 5.1 (IC50 8.4x10-6 M) [5]
View species-specific inhibitor tables
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: ...1

Key to terms and symbols Click column headers to sort
Target used in screen: nd/NIK(MAP3K14)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 29.1
K-252a Hs Inhibitor Inhibition 46.6
DMBI Hs Inhibitor Inhibition 67.7
herbimycin A Hs Inhibitor Inhibition 67.9
TWS119 Hs Inhibitor Inhibition 69.6
JAK inhibitor I Hs Inhibitor Inhibition 71.3
GTP-14564 Hs Inhibitor Inhibition 71.8
DNA-PK inhibitor V Hs Inhibitor Inhibition 75.1
GSK-3 inhibitor X Hs Inhibitor Inhibition 75.7
diacylglycerol kinase inhibitor II Hs Inhibitor Inhibition 75.7
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
NIK is a kinase that operates downstream of several TNF family receptors, including BAFF (TNFRSF13C), TWEAK (TNFRSF12A), CD40 (TNFRSF5), and OX40 (TNFRSF4), and which mediates non-canonical NF-κB signaling. BAFF, TWEAK, CD40, and OX40 are implicated in the pathogenesis of inflammatory diseases including systemic lupus erythematosus (SLE) [2]. NIK is also an anti-cancer drug target [5].
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0033209 tumor necrosis factor-mediated signaling pathway TAS
General Comments
Selective inhibition of NIK as a mechanism to disrupt the non-canonical NF-κB pathway is being investigated as a potential oncology intervention [5].

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Brightbill HD, Suto E, Blaquiere N, Ramamoorthi N, Sujatha-Bhaskar S, Gogol EB, Castanedo GM, Jackson BT, Kwon YC, Haller S et al.. (2018) NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nat Commun, 9 (1): 179. [PMID:29330524]

3. de Leon-Boenig G, Bowman KK, Feng JA, Crawford T, Everett C, Franke Y, Oh A, Stanley M, Staben ST, Starovasnik MA et al.. (2012) The crystal structure of the catalytic domain of the NF-κB inducing kinase reveals a narrow but flexible active site. Structure, 20 (10): 1704-14. [PMID:22921830]

4. Li K, McGee LR, Fisher B, Sudom A, Liu J, Rubenstein SM, Anwer MK, Cushing TD, Shin Y, Ayres M et al.. (2013) Inhibiting NF-κB-inducing kinase (NIK): discovery, structure-based design, synthesis, structure-activity relationship, and co-crystal structures. Bioorg. Med. Chem. Lett., 23 (5): 1238-44. [PMID:23374866]

5. Pippione AC, Sainas S, Federico A, Lupino E, Piccinini M, Kubbutat M, Contreras J-M, Morice C, Barge A, Ducirne A et al.. (2018) N-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK. Med. Chem. Commun., Advance Article. DOI: 10.1039/C8MD00068A

How to cite this page

STE-unique family: mitogen-activated protein kinase kinase kinase 14. Last modified on 30/05/2018. Accessed on 21/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2074.