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mitogen-activated protein kinase kinase kinase 14

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2074

Nomenclature: mitogen-activated protein kinase kinase kinase 14

Abbreviated Name: NIK

Family: STE-unique family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 947 17q21.31 MAP3K14 mitogen-activated protein kinase kinase kinase 14
Mouse - 942 11 66.8 cM 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 Click here for help
NF-κB-inducing kinase | NIK
Database Links Click here for help
Alphafold Q99558 (Hs), Q9WUL6 (Mm)
BRENDA 2.7.11.25
ChEMBL Target CHEMBL5888 (Hs), CHEMBL4523500 (Mm)
Ensembl Gene ENSG00000006062 (Hs), ENSMUSG00000020941 (Mm), ENSRNOG00000003278 (Rn)
Entrez Gene 9020 (Hs), 53859 (Mm), 360640 (Rn)
Human Protein Atlas ENSG00000006062 (Hs)
KEGG Enzyme 2.7.11.25
KEGG Gene hsa:9020 (Hs), mmu:53859 (Mm), rno:360640 (Rn)
OMIM 604655 (Hs)
Pharos Q99558 (Hs)
RefSeq Nucleotide NM_003954 (Hs), NM_016896 (Mm), NM_001108301 (Rn)
RefSeq Protein NP_003945 (Hs), NP_058592 (Mm), NP_001101771 (Rn)
SynPHARM 81639 (in complex with compound 31 [PMID: 23374866])
UniProtKB Q99558 (Hs), Q9WUL6 (Mm)
Wikipedia MAP3K14 (Hs)
Selected 3D Structures Click here for help
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:  5
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:  6
Enzyme Reaction Click here for help
EC Number: 2.7.11.25

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
NIK SMI1 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.6 pKi 3
⤷ pKi 9.6 (Ki 2.3x10-10 M) [3]
NIK SMI1 Small molecule or natural product Immunopharmacology Ligand Mm Inhibition 9.4 pKi 3
⤷ pKi 9.4 (Ki 3.95x10-10 M) [3]
AMG28 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >6.0 pKi 4
⤷ pKi >6.0 (Ki <1x10-6 M) [4]
Description: Enzymatic inhibition determined in a homogenous time resolved fluorescence (HTRF) assay for NIK (MAP3K14)
NIK inhibitor 12f Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 8
⤷ pIC50 8.0 (IC50 9.87x10-9 M) [8]
Description: Inhibition of enzyme activity in a biochemical assay.
compound 31 [PMID: 23374866] Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.7 pIC50 6
⤷ pIC50 7.7 (IC50 2x10-8 M) [6]
compound 18 [PMID: 34212719] Small molecule or natural product Hs Irreversible inhibition 6.7 pIC50 1
⤷ pIC50 6.7 (IC50 2x10-7 M) [1]
compound 3a [Pipionne et al, 2018] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 5.1 pIC50 7
⤷ pIC50 5.1 (IC50 8.4x10-6 M) [7]
View species-specific inhibitor tables
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
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: ...2
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 29.1
K-252a Small molecule or natural product Hs Inhibitor Inhibition 46.6
DMBI Small molecule or natural product Hs Inhibitor Inhibition 67.7
herbimycin A Small molecule or natural product Hs Inhibitor Inhibition 67.9
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 69.6
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 71.3
GTP-14564 Small molecule or natural product Hs Inhibitor Inhibition 71.8
DNA-PK inhibitor V Small molecule or natural product Hs Inhibitor Inhibition 75.1
GSK-3 inhibitor X Small molecule or natural product Hs Inhibitor Inhibition 75.7
diacylglycerol kinase inhibitor II Small molecule or natural product 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) [3]. NIK is also an anti-cancer drug target [7].
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
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 [1,7].

References

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1. Al-Khawaldeh I, Al Yasiri MJ, Aldred GG, Basmadjian C, Bordoni C, Harnor SJ, Heptinstall AB, Hobson SJ, Jennings CE, Khalifa S et al.. (2021) An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase. J Med Chem, 64 (14): 10001-10018. [PMID:34212719]

2. 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]

3. 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]

4. Chen G, Cushing TD, Fisher B, He X, Li K, Li Z, Mcgee L, Pattaropong V, Faulder P, Seganish JL et al.. (2009) Alkynyl alcohols as kinase inhibitors. Patent number: WO2009158011A1. Assignee: Amgen Inc.. Priority date: 26/06/2008. Publication date: 30/12/2009.

5. 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]

6. 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]

7. Pippione AC, Sainas S, Federico A, Lupino E, Piccinini M, Kubbutat M, Contreras JM, Morice C, Barge A, Ducime A et al.. (2018) N-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK. Medchemcomm, 9 (6): 963-968. DOI: 10.1039/C8MD00068A [PMID:30108985]

8. Zhu Y, Ma Y, Zu W, Song J, Wang H, Zhong Y, Li H, Zhang Y, Gao Q, Kong B et al.. (2020) Identification of N-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as Novel, Potent, and Selective NF-κB Inducing Kinase (NIK) Inhibitors for the Treatment of Psoriasis. J Med Chem, 63 (13): 6748-6773. [PMID:32479083]

How to cite this page

STE-unique family: mitogen-activated protein kinase kinase kinase 14. Last modified on 20/09/2022. Accessed on 04/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2074.