MAP3K14

Summary

MAP3K14 (mitogen-activated protein kinase kinase kinase 14, HGNC:6853) is a protein-coding gene on chromosome 17q21.31, encoding Mitogen-activated protein kinase kinase kinase 14 (Q99558). Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity.

This gene encodes mitogen-activated protein kinase kinase kinase 14, which is a serine/threonine protein-kinase. This kinase binds to TRAF2 and stimulates NF-kappaB activity. It shares sequence similarity with several other MAPKK kinases. It participates in an NF-kappaB-inducing signalling cascade common to receptors of the tumour-necrosis/nerve-growth factor (TNF/NGF) family and to the interleukin-1 type-I receptor.

Source: NCBI Gene 9020 — RefSeq curated summary.

At a glance

• Gene–disease (curated): NIK deficiency (Strong, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 455 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003954

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6853
Approved symbol	MAP3K14
Name	mitogen-activated protein kinase kinase kinase 14
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	NIK, HSNIK, FTDCR1B, HS
Ensembl gene	ENSG00000006062
Ensembl biotype	protein_coding
OMIM	604655
Entrez	9020

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000344686, ENST00000376926, ENST00000586644, ENST00000592267, ENST00000617331, ENST00000680632, ENST00000902452, ENST00000902453, ENST00000970422, ENST00000970423, ENST00000970424, ENST00000970425, ENST00000970426

RefSeq mRNA: 1 — MANE Select: NM_003954 NM_003954

CCDS: CCDS74079

Canonical transcript exons

ENST00000344686 — 16 exons

Exon	Start	End
ENSE00000733712	45286431	45287045
ENSE00003464599	45289236	45289305
ENSE00003469334	45266537	45266681
ENSE00003506102	45274464	45274593
ENSE00003525014	45271058	45271221
ENSE00003572718	45274123	45274254
ENSE00003592918	45287154	45287364
ENSE00003627464	45273503	45273607
ENSE00003630119	45267092	45267198
ENSE00003643411	45270413	45270563
ENSE00003653320	45265163	45265263
ENSE00003661311	45290490	45290765
ENSE00003663705	45284812	45284949
ENSE00003677869	45267406	45267759
ENSE00003739529	45316960	45317020
ENSE00003838706	45263119	45264800

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 89.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2658 / max 627.0108, expressed in 1699 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166534	12.2658	1699

Top tissues by expression

266 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	89.95	gold quality
gastrocnemius	UBERON:0001388	89.57	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.29	gold quality
muscle of leg	UBERON:0001383	87.78	gold quality
apex of heart	UBERON:0002098	87.68	gold quality
mucosa of stomach	UBERON:0001199	84.97	gold quality
lymph node	UBERON:0000029	84.79	gold quality
lower esophagus mucosa	UBERON:0035834	84.20	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.12	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.10	gold quality
sigmoid colon	UBERON:0001159	83.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.77	gold quality
lower esophagus	UBERON:0013473	83.75	gold quality
tibialis anterior	UBERON:0001385	83.56	silver quality
spleen	UBERON:0002106	83.27	gold quality
right atrium auricular region	UBERON:0006631	83.06	gold quality
adenohypophysis	UBERON:0002196	82.93	gold quality
transverse colon	UBERON:0001157	82.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.41	gold quality
body of stomach	UBERON:0001161	82.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.23	gold quality
monocyte	CL:0000576	82.07	gold quality
leukocyte	CL:0000738	81.99	gold quality
small intestine	UBERON:0002108	81.96	gold quality
left uterine tube	UBERON:0001303	81.95	gold quality
esophagus	UBERON:0001043	81.94	gold quality
mononuclear cell	CL:0000842	81.63	gold quality
mucosa of transverse colon	UBERON:0004991	81.36	gold quality
heart left ventricle	UBERON:0002084	81.33	gold quality
blood	UBERON:0000178	80.89	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.33

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, E2F1, ESR1, HNF1B, HSF1, IRF6, KLF5, NFKB2, NFKB, NFKBIA, NFKBIB, NR2C2, PPARG, RELA, SKIL, STAT1, TBP, TP53, WNT5A, ZFPM2

miRNA regulators (miRDB)

107 targeting MAP3K14, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777

Literature-anchored findings (GeneRIF, showing 40)

• results demonstrate that IKK2 is essential for dendritic cell activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals (PMID:12393548)
• induction of noncanonical NF-kappaB signaling may involve the rescue of NIK from TRAF3-mediated negative regulation (PMID:15084608)
• subcellular distribution of NIK to different compartments might be a means of regulating the function of this kinase (PMID:15252129)
• Results for the first time place NF-kappa B-inducing kinase (NIK), previously shown to function in TNF signaling, within the interferon signal transduction pathway (PMID:16009713)
• in addition to activating NF-kappaB/p52, LIGHT also activates Stat3 through the NIK pathway (PMID:17543278)
• This study demonstrates that NF-kappaB-inducing kinase (NIK) is a critical target of the endogenous ROS in NF-kappaB pathways. (PMID:17729113)
• NF-kappaB-inducing kinase phosphorylates and blocks the degradation of Down syndrome candidate region 1 (PMID:18056702)
• NIK functions downstream of Cot to mediate p65 phosphorylation. (PMID:18439422)
• Translocation of NF-kappa B to the nucleus in prostatic cancer might be due to overexpression of several components of the NIK pathway. (PMID:18752500)
• Report suppression of hepatitis B virus-derived human hepatocellular carcinoma by NF-kappaB-inducing kinase-specific siRNA using liver-targeting liposomes. (PMID:19641890)
• These results clearly indicate that NIK is involved in the constitutive activation of the alternative pathway and controls cell proliferation in pancreatic cancer cells. (PMID:19646419)
• These findings indicate an upstream signaling role for BCL10, in addition to its effects on IKKgamma, the regulatory component of the IKK signalosome, and a requirement for BCL10 in both canonical and noncanonical pathways of NF-kappaB activation. (PMID:19897484)
• Data provide analysis of the IKK/NIK inter-relationship and its impact on NF-kappaB control by mathematical modelling. (PMID:19909783)
• These results suggest that augmentation of NF-kappaB-inducing kinase, IkappaB kinase-alpha, and pH3 in response to oxidative stress is involved in cell death after cerebral ischemia (or stroke). (PMID:20125184)
• plays a key role in constitutive NF-kappaB activation in non-small cell lung cancer cells (PMID:20338663)
• the LTbetaR modifies the ubiquitin:NIK E3 ligase, and also acts as an allosteric regulator of the ubiquitin:TRAF E3 ligase (PMID:20348096)
• Lipopolysaccharide induces activation of both canonical and non-canonical pathways of NF-kappaB and the non-canonical pathway requires phosphorylations of BCL10 (serine 138) and NIK. (PMID:20466000)
• Data show that NIK with mutations in the IKKalpha-targeted serine residues was more stable than wild-type NIK and resulted in increased noncanonical NF-kappaB signaling. (PMID:20501937)
• An atypical E3 ligase zinc finger protein 91 stabilizes and activates NF-kappaB-inducing kinase via Lys63-linked ubiquitination. (PMID:20682767)
• Data suggest that NIK and genes induced by the NIK-mediated constitutive NF-kappaB activation could be therapeutic targets of basal-like breast cancer. (PMID:20735436)
• Results show that nuclear factor-kappa B inducing kinase has a role in graft-versus-host disease by maintaining the viability of activated alloreactive T lymphocytes. (PMID:20823135)
• TNF-alpha and carrageenan in combination act to increase NIK phosphorylation, thereby increasing activation of the non-canonical pathway of NF-kappaB activation (PMID:20937806)
• findings suggest that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients, perhaps due to altered regulation of NF-kappaB pathway genes, including CXCL10 (PMID:21257964)
• study shows API2-MALT1 fusion oncoprotein induces proteolytic cleavage of NF-kappaB-inducing kinase (NIK); resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappaB signaling, enhanced B cell adhesion and apoptosis resistance (PMID:21273489)
• Adiponectin treatment inhibited NIK-induced NF-kappaB activation and restored insulin sensitivity by restoring phosphatidylinositol 3 kinase activation and subsequent serine-threonine kinase phosphorylation. (PMID:21846802)
• A role for NF-kappaB noncanonical pathway activation in modulating diabetes-induced inflammation in renal tubular epithelium. (PMID:21869881)
• Cigarette smoke and TNFalpha increase NIK levels causing phosphorylation of IKKalpha, which leads to histone acetylation. (PMID:21887257)
• NIK mediates both beta-catenin and NF-kappaB regulated transcription to modulate melanoma survival and growth (PMID:21963849)
• NIK is one of the direct target genes of miR-520e. (PMID:22105365)
• Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. (PMID:22469134)
• NIK activity in nonhematopoietic cells controls Th2 cell development and prevents eosinophil-driven inflammatory disease, most likely using a signaling pathway that operates independent of the known NIK substrate IKKalpha. (PMID:22474019)
• APPL1 regulates basal NF-kappaB activity by modulating the stability of NIK, which affects the activation of p65. (PMID:22685329)
• a molecular basis for the recent observation of gain-of-function activity for an N-terminal deletion mutant (DeltaN324) of NIK, leading to constitutive non-canonical NF-kappaB signaling with enhanced B-cell adhesion and apoptosis resistance. (PMID:22718757)
• we found that NIK and the noncanonical pathway are very prevalent in Hodgkin lymphoma (PMID:22968463)
• TRAF2/NIK/NF-kappaB2 pathway regulates pancreatic ductal adenocarcinoma cell tumorigenicity (PMID:23301098)
• A pivotal role for NIK in nuclear factor kappa B activation and regulation of gene expression in T-cell lymphoma. (PMID:23536439)
• NIK is a new therapeutic target for Mantle cell lymphoma treatment, particularly for lymphomas that are refractory to B cell receptor pathway inhibitors. (PMID:24362935)
• NIK plays a key role in constitutive NF-kappaB activation and the progression of ovarian cancer cells (PMID:24533079)
• These studies provide evidence for a role of NF-kappaB-inducing kinase (NIK) and subsequent non-canonical NF-kappaB signalling in pathological angiogenesis (PMID:25043127)
• ARC is regulated via BIRC2/MAP3K14 signalling and its overexpression in AML or MSCs can function as a resistant factor to birinapant-induced leukaemia cell death. (PMID:25079338)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k14b	ENSDARG00000056582
danio_rerio	map3k14a	ENSDARG00000074060
mus_musculus	Map3k14	ENSMUSG00000020941
rattus_norvegicus	Map3k14	ENSRNOG00000003278

Paralogs (35): MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), NEK4 (ENSG00000114904), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), PAK1 (ENSG00000149269), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 14 — Q99558 (reviewed: Q99558)

Alternative names: NF-kappa-beta-inducing kinase, Serine/threonine-protein kinase NIK

All UniProt accessions (3): Q99558, A0A087WXF1, A0A7P0Z419

UniProt curated annotations — full annotation on UniProt →

Function. Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Phosphorylates CHUK/IKKA, thereby promoting proteolytic processing of NFKB2/P100, which leads to NF-kappa-B activation via the non-canonical pathway. Has an essential role in the non-canonical NF-kappa-B signaling that regulates genes encoding molecules involved in B-cell survival, lymphoid organogenesis, and immune response. Could act in a receptor-selective manner.

Subunit / interactions. Interacts with TRAF2, TRAF5, TRAF6, IKKA and NFKB2/P100. Interacts with TRAF3 and PELI3. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts with ZFP91. Interacts with NLRP12; this interaction promotes proteasomal degradation of MAP3K14. Directly interacts with DDX3X. Interacts (via C-terminus and kinase domain) with PPPC3A (via N-terminus) and PPP3CB.

Subcellular location. Cytoplasm.

Tissue specificity. Weakly expressed in testis, small intestine, spleen, thymus, peripheral blood leukocytes, prostate, ovary and colon.

Post-translational modifications. Autophosphorylated. Phosphorylation at Thr-559 is required to activate its kinase activity and ‘Lys-63’-linked polyubiquitination. Phosphorylated by CHUK/IKKA leading to MAP3K14 destabilization. Ubiquitinated. Undergoes both ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination. ‘Lys-48’-linked polyubiquitination leads to its degradation by the proteasome, while ‘Lys-63’-linked polyubiquitination stabilizes and activates it.

Disease relevance. Immunodeficiency 112 (IMD112) [MIM:620449] An autosomal recessive, primary immunologic disorder characterized by variable abnormalities affecting lymphoid immunity, including hypogammaglobulinemia, lymphopenia or paradoxical lymphocytosis, and recurrent bacterial, viral, and fungal infections. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

RefSeq proteins (1): NP_003945* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017425	MAPKKK14	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR042787	M3K14_STKc	Domain
IPR050538	MAP_kinase_kinase_kinase	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (63 total): helix 15, strand 11, sequence variant 9, turn 7, compositionally biased region 5, region of interest 5, sequence conflict 3, binding site 2, mutagenesis site 2, chain 1, domain 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6Z1T	X-RAY DIFFRACTION	2.31
4IDT	X-RAY DIFFRACTION	2.4
6Z1Q	X-RAY DIFFRACTION	2.42
4DN5	X-RAY DIFFRACTION	2.5
6WPP	X-RAY DIFFRACTION	2.55
4G3D	X-RAY DIFFRACTION	2.9
4IDV	X-RAY DIFFRACTION	2.9
8YHW	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99558-F1	61.00	0.31

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 515 (proton acceptor)

Ligand- & substrate-binding residues (2): 406–414; 429

Post-translational modifications (1): 559

Mutagenesis-validated functional residues (2):

Position	Phenotype
429–430	loss of autophosphorylation and ’lys-63’-linked ubiquitination. unable to phosphorylate chuk/ikka.
559	abolishes ’lys-63’-linked ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-389357	CD28 dependent PI3K/Akt signaling
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-5676590	NIK–>noncanonical NF-kB signaling
R-HSA-5676594	TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-388841	Regulation of T cell activation by CD28 family
R-HSA-389356	Co-stimulation by CD28
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5621481	C-type lectin receptors (CLRs)

MSigDB gene sets: 331 (showing top): BIOCARTA_TNFR2_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, BIOCARTA_RNA_PATHWAY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, KEGG_MAPK_SIGNALING_PATHWAY, NAGASHIMA_NRG1_SIGNALING_UP, REACTOME_CO_STIMULATION_BY_CD28, BIOCARTA_IL1R_PATHWAY, CAIRO_HEPATOBLASTOMA_CLASSES_DN, LINDSTEDT_DENDRITIC_CELL_MATURATION_B, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, AMIT_EGF_RESPONSE_120_HELA, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (7): MAPK cascade (GO:0000165), immune response (GO:0006955), non-canonical NF-kappaB signal transduction (GO:0038061), defense response to virus (GO:0051607), cellular response to mechanical stimulus (GO:0071260), protein phosphorylation (GO:0006468), intracellular signal transduction (GO:0035556)

GO Molecular Function (9): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): fibrillar center (GO:0001650), nucleoplasm (GO:0005654), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Immune System	3
TNFR2 non-canonical NF-kB pathway	2
Co-stimulation by CD28	1
CLEC7A (Dectin-1) signaling	1
Cytokine Signaling in Immune system	1
Adaptive Immune System	1
Regulation of T cell activation by CD28 family	1
C-type lectin receptors (CLRs)	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular signaling cassette	2
intracellular anatomical structure	2
protein kinase activity	2
immune system process	1
response to stimulus	1
defense response	1
response to virus	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
phosphorylation	1
protein modification process	1
signal transduction	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
MAPK cascade	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
nucleolus	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

2659 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K14	NFKBIA	P25963	789
MAP3K14	NFKB2	Q00653	770
MAP3K14	RELA	Q04206	763
MAP3K14	TNFRSF13C	Q96RJ3	761
MAP3K14	RELB	Q01201	752
MAP3K14	TRAF2	Q12933	720
MAP3K14	CHUK	O15111	710
MAP3K14	TRAF6	Q9Y4K3	702
MAP3K14	TRAPPC9	Q96Q05	684
MAP3K14	LTBR	P36941	682
MAP3K14	IKBKG	Q9Y6K9	666
MAP3K14	NFKB1	P19838	650
MAP3K14	TNFSF13B	Q9Y275	598
MAP3K14	CD40	P25942	585
MAP3K14	TRAF3	Q13114	584

IntAct

167 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0217”(phosphorylation reaction)	0.950
MAP3K14	CHUK	psi-mi:“MI:0915”(physical association)	0.950
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
CHUK	MAP3K14	psi-mi:“MI:2364”(proximity)	0.950
CHUK	MAP3K14	psi-mi:“MI:0217”(phosphorylation reaction)	0.950
TRAF3	MAP3K14	psi-mi:“MI:0915”(physical association)	0.920
MAP3K14	IKBKB	psi-mi:“MI:0217”(phosphorylation reaction)	0.900
IKBKB	MAP3K14	psi-mi:“MI:0915”(physical association)	0.900
MAP3K14	IKBKB	psi-mi:“MI:0914”(association)	0.900
MAP3K14	CDC37	psi-mi:“MI:0915”(physical association)	0.810
MAP3K14	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.760
MAP3K14	TRAF2	psi-mi:“MI:0915”(physical association)	0.750
TRAF2	MAP3K14	psi-mi:“MI:0915”(physical association)	0.750
MAP3K14	TRAF2	psi-mi:“MI:0407”(direct interaction)	0.750
LTBR	TRAF2	psi-mi:“MI:0914”(association)	0.670
CHUK	MAP3K7	psi-mi:“MI:0914”(association)	0.650
MAP3K14	HRAS	psi-mi:“MI:0915”(physical association)	0.560
Chuk	MAP3K14	psi-mi:“MI:0915”(physical association)	0.540
Chuk	MAP3K14	psi-mi:“MI:0407”(direct interaction)	0.540

BioGRID (268): BIRC2 (Affinity Capture-Western), TRAF2 (Affinity Capture-Western), TRAF3 (Affinity Capture-Western), MAP3K14 (Affinity Capture-Western), MAP3K14 (Two-hybrid), BRCA1 (Two-hybrid), MAP3K14 (Reconstituted Complex), MAP3K14 (Affinity Capture-Western), SLC9A1 (Biochemical Activity), MAP3K14 (Affinity Capture-Western), TRAF6 (Co-localization), CHUK (Co-localization), CASP3 (Co-localization), CHUK (Affinity Capture-MS), IKBKB (Affinity Capture-MS)

ESM2 similar proteins: A0A0A6YY25, A6NGG8, A6X8Z5, B2RQL2, B2RXH4, D3ZMK9, D3ZUE1, E9Q7F2, O08696, O14513, P59598, P97691, Q05860, Q05AH6, Q08050, Q0GGX2, Q0VET5, Q13029, Q2M1Z3, Q3U0P1, Q571I4, Q5PSV9, Q5SSG4, Q5U2M8, Q5VV67, Q63755, Q66H04, Q68DA7, Q69ZL1, Q6DIA7, Q6JPI3, Q6P1D7, Q6PAC4, Q6PG16, Q71F56, Q76N32, Q811R2, Q86YN6, Q86YV5, Q8BJS7

Diamond homologs: A2AAJ9, A3LN91, A4PES0, A4QNA8, A5D791, A7A1P0, B5VNQ3, D0Z5N4, D2HHP1, E1BTE1, E2RSS3, F4HPN2, G5ECH7, O13889, O18209, O57473, O77819, O88850, P07527, P08458, P09759, P0C1S8, P15442, P19525, P20793, P20794, P22216, P23561, P27466, P30291, P33279, P47810, P47817, P54350, P54665, P54666, P54762, P70335, P74297, P83100

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
MAP3K14	“up-regulates activity”	NFKB2	phosphorylation
CHUK	“down-regulates quantity by destabilization”	MAP3K14	phosphorylation
MAP3K14	“up-regulates activity”	CHUK	phosphorylation
MAP3K14	“up-regulates activity”	MAP3K14	phosphorylation
TRAF2	“down-regulates quantity by destabilization”	MAP3K14	ubiquitination
BIRC3	down-regulates	MAP3K14	ubiquitination
ZFP91	up-regulates	MAP3K14	ubiquitination
MAP3K14	up-regulates	IKK-complex	phosphorylation
MAP3K8	“up-regulates activity”	MAP3K14	phosphorylation
TRAF6	“up-regulates activity”	MAP3K14	binding
TRAPPC9	“up-regulates activity”	MAP3K14	binding
MAP3K14	“up-regulates activity”	G6PD	phosphorylation
TRAF3	“down-regulates quantity by destabilization”	MAP3K14	ubiquitination
MAP3K14	“up-regulates activity”	STAT3	phosphorylation
MAP3K14	“up-regulates activity”	MMP14	phosphorylation
MAP3K14	“up-regulates activity”	SLC9A1	phosphorylation
TBK1	“down-regulates quantity by destabilization”	MAP3K14	phosphorylation
MAP3K14	up-regulates	NfKb-p65/p50
TRAF2	“up-regulates activity”	MAP3K14	binding
MAP3K14	up-regulates	IKBKB	phosphorylation
TRAF2	“down-regulates quantity by destabilization”	MAP3K14	binding
TRAF3	“down-regulates quantity by destabilization”	MAP3K14	binding
MAP3K7	“up-regulates activity”	MAP3K14	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 modulates host translation machinery	21	54.9×	1e-31
Eukaryotic Translation Initiation	19	49.7×	2e-27
Cap-dependent Translation Initiation	19	49.7×	2e-27
Peptide chain elongation	44	47.3×	2e-63
Eukaryotic Translation Elongation	20	47.2×	3e-28
Viral mRNA Translation	43	46.2×	1e-61
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	43	45.7×	2e-61
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	44	43.9×	1e-61

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	42	63.8×	5e-65
positive regulation of cytoplasmic translation	5	40.6×	1e-05
cytoplasmic pattern recognition receptor signaling pathway	5	36.4×	2e-05
protein refolding	7	35.8×	9e-08
translation	42	35.4×	3e-52
non-canonical NF-kappaB signal transduction	5	34.5×	2e-05
alternative mRNA splicing, via spliceosome	6	33.1×	2e-06
ribosomal small subunit biogenesis	17	31.7×	7e-19

Disease & clinical

Clinical variants and AI predictions

ClinVar

455 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	179
Likely benign	237
Benign	11

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3233307	NM_003954.5(MAP3K14):c.1694C>G (p.Pro565Arg)	Pathogenic
1489957	NM_003954.5(MAP3K14):c.916del (p.Cys306fs)	Likely pathogenic

SpliceAI

2208 predictions. Top by Δscore:

Variant	Effect	Δscore
17:45265157:CCTTA:C	donor_loss	1.0000
17:45265158:CTTA:C	donor_loss	1.0000
17:45265159:TTACC:T	donor_loss	1.0000
17:45265160:TAC:T	donor_loss	1.0000
17:45265161:ACC:A	donor_loss	1.0000
17:45265162:CCT:C	donor_loss	1.0000
17:45265162:CCTGG:C	donor_gain	1.0000
17:45265259:CACAC:C	acceptor_gain	1.0000
17:45265260:ACAC:A	acceptor_gain	1.0000
17:45265261:CAC:C	acceptor_gain	1.0000
17:45265261:CACC:C	acceptor_gain	1.0000
17:45265262:AC:A	acceptor_gain	1.0000
17:45265262:ACC:A	acceptor_loss	1.0000
17:45265263:CC:C	acceptor_gain	1.0000
17:45265264:C:CC	acceptor_gain	1.0000
17:45265264:CT:C	acceptor_loss	1.0000
17:45267088:TCAC:T	donor_loss	1.0000
17:45267090:A:AC	donor_gain	1.0000
17:45267090:AC:A	donor_gain	1.0000
17:45267091:C:CA	donor_loss	1.0000
17:45267091:C:CC	donor_gain	1.0000
17:45267091:CC:C	donor_gain	1.0000
17:45267091:CCTT:C	donor_gain	1.0000
17:45267194:TAATT:T	acceptor_gain	1.0000
17:45267195:AATT:A	acceptor_gain	1.0000
17:45267196:ATT:A	acceptor_gain	1.0000
17:45267196:ATTC:A	acceptor_loss	1.0000
17:45267197:TT:T	acceptor_gain	1.0000
17:45267198:TCTG:T	acceptor_loss	1.0000
17:45267199:C:CC	acceptor_gain	1.0000

AlphaMissense

6163 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:45264674:A:G	W936R	0.999
17:45264674:A:T	W936R	0.999
17:45271139:C:A	W580C	0.999
17:45271139:C:G	W580C	0.999
17:45271141:A:G	W580R	0.999
17:45271141:A:T	W580R	0.999
17:45273559:T:A	D534V	0.999
17:45284815:T:A	K429N	0.999
17:45284815:T:G	K429N	0.999
17:45265182:G:T	A887D	0.998
17:45271091:C:A	W596C	0.998
17:45271091:C:G	W596C	0.998
17:45271093:A:G	W596R	0.998
17:45271093:A:T	W596R	0.998
17:45271133:G:C	S582R	0.998
17:45271133:G:T	S582R	0.998
17:45271135:T:G	S582R	0.998
17:45273558:G:C	D534E	0.998
17:45273558:G:T	D534E	0.998
17:45273559:T:G	D534A	0.998
17:45274125:T:A	K517I	0.998
17:45284816:T:A	K429I	0.998
17:45264667:A:T	V938D	0.997
17:45264669:C:A	R937S	0.997
17:45264669:C:G	R937S	0.997
17:45264715:A:G	L922P	0.997
17:45270464:G:T	R641S	0.997
17:45271127:A:C	C584W	0.997
17:45273559:T:C	D534G	0.997
17:45274124:T:A	K517N	0.997

dbSNP variants (sampled 300 via entrez): RS1000086031 (17:45294504 C>T), RS1000094834 (17:45310483 G>T), RS1000113123 (17:45309844 T>C), RS1000114831 (17:45314617 AG>A), RS1000168568 (17:45310159 G>A), RS1000173039 (17:45281866 G>C), RS1000288271 (17:45275813 G>A), RS1000323241 (17:45316999 C>T), RS1000335712 (17:45263553 A>G), RS1000430018 (17:45303834 G>A,C), RS1000436766 (17:45315007 T>C), RS1000468697 (17:45279216 G>A), RS1000476326 (17:45294980 G>A,T), RS1000541007 (17:45285356 T>G), RS1000573547 (17:45285612 T>G)

Disease associations

OMIM: gene MIM:604655 | disease phenotypes: MIM:620449

GenCC curated gene-disease

Disease	Classification	Inheritance
NIK deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
NIK deficiency	Moderate	AR

Mondo (2): NIK deficiency (MONDO:0018642), immunodeficiency 112 (MONDO:0957535)

Orphanet (1): NIK deficiency (Orphanet:447731)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002028	Chronic diarrhea
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002728	Chronic mucocutaneous candidiasis
HP:0002783	Recurrent lower respiratory tract infections
HP:0002850	Decreased circulating total IgM
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004429	Recurrent viral infections
HP:0005403	Decreased total T cell count
HP:0005404	Increased total B cell count
HP:0010976	Decreased total B cell count
HP:0011463	Childhood onset
HP:0020086	BCGitis
HP:0020087	BCGosis
HP:0030388	Decreased class-switched memory B cell proportion
HP:0040218	Reduced total natural killer cell count
HP:0100828	Increased total T cell count
HP:0500271	Decreased gamma-delta T cell proportion

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001198_49	Multiple sclerosis	3.000000e-06
GCST004077_9	Cognitive function	1.000000e-07
GCST005038_99	Allergic disease (asthma, hay fever or eczema)	1.000000e-08
GCST006661_255	Male-pattern baldness	2.000000e-22
GCST007123_3	Multiple sclerosis and LDL levels (pleiotropy)	5.000000e-06
GCST007797_25	Asthma onset (childhood vs adult)	7.000000e-10
GCST007798_102	Asthma	6.000000e-07
GCST007800_70	Asthma (childhood onset)	6.000000e-20
GCST008643_1	Joint damage in rheumatoid arthritis	6.000000e-06
GCST008916_39	Asthma	8.000000e-12
GCST009325_102	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	8.000000e-27
GCST009597_223	Multiple sclerosis	2.000000e-10
GCST009720_68	Asthma	2.000000e-11
GCST009798_36	Asthma	2.000000e-10
GCST90002400_217	Plateletcrit	2.000000e-16

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004847	age at onset
EFO:0005413	joint damage measurement
EFO:0007985	platelet crit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5888 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 18 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL4277900	CROZBACICLIB	2	18

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7222094	MAP3K14		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — STE-unique family

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
NIK SMI1	Inhibition	9.64	pKi
NIK inhibitor 12f	Inhibition	8.01	pIC50
compound 31 [PMID: 23374866]	Inhibition	7.7	pIC50
compound 18 [PMID: 34212719]	Irreversible inhibition	6.7	pIC50
AMG28	Inhibition	6.0	pKi
compound 3a [Pipionne et al, 2018]	Inhibition	5.08	pIC50

Binding affinities (BindingDB)

587 measured of 659 human assays (659 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
9-[2-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.04 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.055 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-3-[(S)-hydroxy-(2-methylpyrazol-3-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.1 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-3-[(R)-hydroxy-(2-methylpyrazol-3-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.1 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4S)-9-[2-[(3R)-3-hydroxy-2-oxopyrrolidin-3-yl]ethynyl]-4-methyl-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.1 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4R)-9-[2-[(3R)-3-hydroxy-2-oxopyrrolidin-3-yl]ethynyl]-4-methyl-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.1 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-(3-hydroxy-3-methylbut-1-ynyl)-3-N-methyl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide	KI	0.12 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-fluoro-10-[2-(1-hydroxycyclopentyl)ethynyl]-3-N-methyl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide	KI	0.12 nM	US-9034866: Tricyclic compounds and methods of use therefor
8-fluoro-9-[(3R)-3-hydroxy-3-pyrimidin-2-ylbut-1-ynyl]-3-methyl-4,5,6,11-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide	KI	0.16 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.2 nM	US-9034866: Tricyclic compounds and methods of use therefor
8-fluoro-9-[2-(1-hydroxycyclopentyl)ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.2 nM	US-9034866: Tricyclic compounds and methods of use therefor
8-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-4,5,6,11-tetrahydro-3H-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide	KI	0.2 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[2-(1-hydroxycyclobutyl)ethynyl]-3-N-methyl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide	KI	0.2 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-3-[(2-methylpyrazol-3-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.2 nM	US-9034866: Tricyclic compounds and methods of use therefor
4,4,8-trifluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-5H-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.2 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-fluoro-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	KI	0.24 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3S)-3-hydroxy-3-(5-methyl-1,3-oxazol-2-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.29 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3R)-3-hydroxy-3-(5-methyl-1,3-oxazol-2-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.29 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	KI	0.3 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-3-N-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide	KI	0.3 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.3 nM	US-9034866: Tricyclic compounds and methods of use therefor
3-(difluoromethyl)-8-fluoro-9-(3-hydroxy-3-methylbut-1-ynyl)-4,5,6,11-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide	KI	0.3 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4R)-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4-methyl-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.3 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4S)-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4-methyl-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.3 nM	US-9034866: Tricyclic compounds and methods of use therefor
3-(difluoromethyl)-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.3 nM	US-9034866: Tricyclic compounds and methods of use therefor
3-cyclopropyl-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.31 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4R)-4-(dimethylamino)-8-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.33 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4S)-4-(dimethylamino)-8-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.33 nM	US-9034866: Tricyclic compounds and methods of use therefor
4,4-difluoro-9-[2-[(3R)-3-hydroxy-2-oxopyrrolidin-3-yl]ethynyl]-5H-pyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.33 nM	US-9034866: Tricyclic compounds and methods of use therefor
4,4-difluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-5H-pyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.33 nM	US-9034866: Tricyclic compounds and methods of use therefor
4,4-difluoro-9-[2-[(3S)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-5H-pyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.33 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4S)-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4-methyl-3-(trifluoromethyl)-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.39 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4R)-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4-methyl-3-(trifluoromethyl)-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.39 nM	US-9034866: Tricyclic compounds and methods of use therefor
3-N-(cyanomethyl)-9-fluoro-10-(3-hydroxy-3-methylbut-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-fluoro-10-(3-hydroxy-3-methylbut-1-ynyl)-3-(3-pyridin-3-yl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-fluoro-10-[2-(1-hydroxycyclobutyl)ethynyl]-3-N-methyl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4S)-9-[(3S)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-4-methyl-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4R)-9-[(3S)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-4-methyl-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4S)-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
(4R)-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
3-chloro-4,4-difluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-5H-pyrazolo[5,1-d][1,5]benzoxazepine-2-carboxamide	KI	0.4 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-3-(trifluoromethyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.5 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-fluoro-10-(3-hydroxy-3-methylbut-1-ynyl)-3-(2-hydroxypropan-2-yl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.5 nM	US-9034866: Tricyclic compounds and methods of use therefor
8-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-3-methyl-4,5,6,11-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide	KI	0.5 nM	US-9034866: Tricyclic compounds and methods of use therefor
8-fluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-3-methyl-4,5,6,11-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide	KI	0.5 nM	US-9034866: Tricyclic compounds and methods of use therefor
8-fluoro-9-[2-[(3S)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-3-methyl-4,5,6,11-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide	KI	0.5 nM	US-9034866: Tricyclic compounds and methods of use therefor
10-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-3-N-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide	KI	0.5 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]spiro[5H-pyrazolo[5,1-d][1,5]benzoxazepine-4,1’-cyclobutane]-2-carboxamide	KI	0.5 nM	US-9034866: Tricyclic compounds and methods of use therefor
8-fluoro-9-[2-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d][1,3]thiazole-2-carboxamide	KI	0.53 nM	US-9034866: Tricyclic compounds and methods of use therefor
9-fluoro-10-[2-(1-hydroxycyclobutyl)ethynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	KI	0.53 nM	US-9034866: Tricyclic compounds and methods of use therefor

ChEMBL bioactivities

1676 potent at pChembl≥5 of 1724 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	Ki	0.04	nM	CHEMBL3696534
10.30	Ki	0.05	nM	CHEMBL4205698
10.30	Ki	0.05	nM	CHEMBL5899570
10.30	Ki	0.05	nM	CHEMBL6027332
10.30	Ki	0.05	nM	CHEMBL5805453
10.30	Ki	0.05	nM	CHEMBL4204233
10.30	Ki	0.05	nM	CHEMBL5887632
10.30	Ki	0.05	nM	CHEMBL4217407
10.30	Ki	0.05	nM	CHEMBL5769590
10.30	Ki	0.05	nM	CHEMBL5876959
10.30	Ki	0.05	nM	CHEMBL5966557
10.30	Ki	0.05	nM	CHEMBL5931694
10.30	Ki	0.05	nM	CHEMBL5978342
10.30	Ki	0.05	nM	CHEMBL6029428
10.30	Ki	0.05	nM	CHEMBL6047001
10.30	Ki	0.05	nM	CHEMBL6020833
10.30	Ki	0.05	nM	CHEMBL5981987
10.30	Ki	0.05	nM	CHEMBL5824850
10.30	Ki	0.05	nM	CHEMBL5858445
10.30	Ki	0.05	nM	CHEMBL5800378
10.30	Ki	0.05	nM	CHEMBL5796189
10.30	Ki	0.05	nM	CHEMBL5994916
10.28	Ki	0.053	nM	CHEMBL5826088
10.26	Ki	0.055	nM	CHEMBL3696579
10.22	Ki	0.06	nM	CHEMBL5951539
10.22	Ki	0.06	nM	CHEMBL5947842
10.15	Ki	0.07	nM	CHEMBL4215425
10.15	Ki	0.07	nM	CHEMBL4216289
10.15	Ki	0.07	nM	CHEMBL4212052
10.15	Ki	0.07	nM	CHEMBL5847498
10.15	Ki	0.07	nM	CHEMBL6036793
10.10	Ki	0.08	nM	CHEMBL4211046
10.10	Ki	0.08	nM	CHEMBL4209095
10.10	Ki	0.08	nM	CHEMBL4211551
10.10	Ki	0.08	nM	CHEMBL5789286
10.05	Ki	0.09	nM	CHEMBL5756517
10.01	Ki	0.098	nM	CHEMBL4211046
10.00	Ki	0.1	nM	CHEMBL4115488
10.00	Ki	0.1	nM	CHEMBL3934782
10.00	Ki	0.1	nM	CHEMBL3700218
10.00	Ki	0.1	nM	CHEMBL3700225
10.00	Ki	0.1	nM	CHEMBL5794660
10.00	Ki	0.1	nM	CHEMBL5792109
10.00	Ki	0.1	nM	CHEMBL5989362
10.00	Ki	0.1	nM	CHEMBL5951181
10.00	Ki	0.1	nM	CHEMBL5776951
10.00	Ki	0.1	nM	CHEMBL5986879
9.96	Ki	0.11	nM	CHEMBL5921690
9.96	Ki	0.11	nM	CHEMBL5867850
9.92	Ki	0.12	nM	CHEMBL3696555

PubChem BioAssay actives

385 with measured affinity, of 660 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-amino-6-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]pyridine-2-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0001	uM
3-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]isoquinoline-1-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0001	uM
1-[4-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2-pyridinyl]indazole-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0001	uM
1-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]-5-methoxypyrazolo[5,4-b]pyridine-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0001	uM
1-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]-6-methoxyimidazo[1,5-a]pyridine-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0001	uM
6-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]-4-methoxypyridine-2-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0002	uM
1-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]pyrazolo[5,4-b]pyridine-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0002	uM
1-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]imidazo[1,5-a]pyridine-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0002	uM
5-fluoro-1-[4-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2-pyridinyl]indazole-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0002	uM
1-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]indazole-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0002	uM
(2R)-4-[3-(2-aminopyrimidin-4-yl)-2-ethoxybenzimidazol-5-yl]-2-(5-methyl-1,3-oxazol-2-yl)but-3-yn-2-ol	1511445: Inhibition of NIK (unknown origin) using ATP as substrate by transcreener ADP assay based fluorescence correlation spectroscopic analysis	ki	0.0002	uM
5-fluoro-1-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]indazole-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0003	uM
(2S)-4-[3-(2-amino-5-chloropyrimidin-4-yl)imidazo[1,2-a]pyridin-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	1413755: Inhibition of NIK (unknown origin) by HTRF method	ki	0.0003	uM
9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0003	uM
6-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]pyridine-2-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0004	uM
4-[1-(2-amino-5-chloropyrimidin-4-yl)-2,3-dihydroindol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	1657818: Inhibition of NIK (unknown origin)	ki	0.0004	uM
9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0004	uM
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-3-N-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0005	uM
2-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]-6-methoxypyrimidine-4-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0006	uM
(3R)-5-[2-[5-[dideuterio(hydroxy)methyl]-2-methylanilino]pyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0008	uM
9-fluoro-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0008	uM
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	1511445: Inhibition of NIK (unknown origin) using ATP as substrate by transcreener ADP assay based fluorescence correlation spectroscopic analysis	ki	0.0008	uM
1-[4-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2-pyridinyl]-4,5,6,7-tetrahydroindazole-3-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0009	uM
1-[3-[2-[(1R,4R,5S)-4-hydroxy-2-methyl-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]ethynyl]phenyl]pyrazolo[5,4-b]pyridine-3-carboxamide	2031249: Inhibition of NIK (unknown origin) catalyzed ATP hydrolysis assessed as inhibition constant by fluorescence polarization method	ki	0.0009	uM
10-[(3R)-3-hydroxy-3-(5-methyl-1,3-oxazol-2-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	1511445: Inhibition of NIK (unknown origin) using ATP as substrate by transcreener ADP assay based fluorescence correlation spectroscopic analysis	ki	0.0009	uM
(3R)-5-[2-(5-cyano-2-methylanilino)-5-fluoropyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379891: Inhibition of MAP3K14 in human L363 assessed as decrease in IKKalpha phosphorylation level after 2 hrs by sandwich immuno assay	ic50	0.0012	uM
6-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]pyrazine-2-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0013	uM
(3R)-5-[2-[5-cyano-2-(hydroxymethyl)anilino]pyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0013	uM
(3R)-5-[2-[5-cyano-2-methyl-4-(2-morpholin-4-ylethyl)anilino]pyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379891: Inhibition of MAP3K14 in human L363 assessed as decrease in IKKalpha phosphorylation level after 2 hrs by sandwich immuno assay	ic50	0.0013	uM
(2R)-4-[4-[2-(3,5-dimethoxyanilino)pyrimidin-4-yl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-2-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	2082979: Inhibition of NIK (unknown origin) incubated 30 to 60 mins by ADP-Glo Kinase	ic50	0.0013	uM
(3R)-3-(hydroxymethyl)-5-[2-[5-(hydroxymethyl)-2-propan-2-yloxyanilino]pyrimidin-4-yl]-3-methyl-1,2-dihydroindole-7-carbonitrile	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0014	uM
9-fluoro-10-[3-hydroxy-3-(1,3-thiazol-2-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0015	uM
3-cyclopropyl-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	1511445: Inhibition of NIK (unknown origin) using ATP as substrate by transcreener ADP assay based fluorescence correlation spectroscopic analysis	ki	0.0017	uM
3-[[4-[(3R)-7-cyano-3-(hydroxymethyl)-3-methyl-1,2-dihydroindol-5-yl]pyrimidin-2-yl]amino]-N,4-dimethylbenzamide	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0018	uM
(3R)-5-[2-(5-cyano-4-fluoro-2-methylanilino)pyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0018	uM
4-[3-[2-[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl]pyrimidine-2-carboxamide	1381316: Inhibition of NIK (unknown origin) expressed in baculovirus infected insect cells assessed as reduction in hydrolysis of ATP to ADP after 1 to 2 hrs by ADP-MR121 633 tracer based fluorescence polarization assay	ki	0.0020	uM
9-fluoro-10-(3-hydroxy-3-methylbut-1-ynyl)-3-N-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0020	uM
(3R)-5-[2-[4-fluoro-5-(hydroxymethyl)-2-methylanilino]pyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0023	uM
4-[4-[2-(1,3-benzodioxol-5-ylamino)pyrimidin-4-yl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-2-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	2082979: Inhibition of NIK (unknown origin) incubated 30 to 60 mins by ADP-Glo Kinase	ic50	0.0029	uM
9-fluoro-10-(3-hydroxy-3-methylbut-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0029	uM
9-fluoro-10-[2-(3-hydroxy-1-methyl-2-oxopiperidin-3-yl)ethynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0030	uM
10-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	1511445: Inhibition of NIK (unknown origin) using ATP as substrate by transcreener ADP assay based fluorescence correlation spectroscopic analysis	ki	0.0031	uM
9-fluoro-10-(3-hydroxy-3-pyridazin-3-ylbut-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide	1483568: Inhibition of NIK (unknown origin) after 1 to 2 hrs by ADP-FP assay	ki	0.0032	uM
4-[4-[2-(1,3-benzodioxol-5-ylamino)pyrimidin-4-yl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-2-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol	2082979: Inhibition of NIK (unknown origin) incubated 30 to 60 mins by ADP-Glo Kinase	ic50	0.0038	uM
(3R)-5-[2-[5-cyano-2-(2-hydroxy-2-methylpropoxy)anilino]pyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0041	uM
(2R)-4-[1-(2-amino-5-chloropyrimidin-4-yl)-2,3-dihydroindol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	1606483: Inhibition of human NIK using ATP as substrate by kinase-glo assay	ic50	0.0042	uM
7-[2-[4-[2-(1,3-benzodioxol-5-ylamino)pyrimidin-4-yl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-2-yl]ethynyl]-5,6-dihydropyrrolo[1,2-a]imidazol-7-ol	2082979: Inhibition of NIK (unknown origin) incubated 30 to 60 mins by ADP-Glo Kinase	ic50	0.0043	uM
4-[4-[2-[(6-methoxy-2-pyridinyl)amino]pyrimidin-4-yl]-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-2-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	2082979: Inhibition of NIK (unknown origin) incubated 30 to 60 mins by ADP-Glo Kinase	ic50	0.0044	uM
(3R)-5-[2-[5-cyano-2-(4-fluoro-1-methylpyrrolidin-3-yl)oxyanilino]pyrimidin-4-yl]-3-(hydroxymethyl)-3-methyl-1,2-dihydroindole-7-carbonitrile	1379892: Inhibition of recombinant human GST-tagged MAP3K14 autophosphorylation after 1 hr by Alpha screen assay	ic50	0.0046	uM
4-[4-(2-aminopyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrimidin-2-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	2082979: Inhibition of NIK (unknown origin) incubated 30 to 60 mins by ADP-Glo Kinase	ic50	0.0046	uM

CTD chemical–gene interactions

88 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	4
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Valproic Acid	affects expression, increases expression	3
perfluorooctane sulfonic acid	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silver	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
2-anisidine	decreases expression	1
tylophorine	increases expression	1
methylmercuric chloride	increases expression	1
hydroxyethyl methacrylate	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects cotreatment, decreases expression	1
mangiferin	decreases phosphorylation	1
arsenite	decreases reaction, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
diallyl trisulfide	decreases expression	1
mercuric bromide	affects cotreatment, increases expression	1
epigallocatechin gallate	decreases expression	1
1’-acetoxychavicol acetate	decreases reaction, increases expression	1

ChEMBL screening assays

143 unique, capped per target: 143 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1038690	Binding	Inhibition of NIK	Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. — J Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1GD	Abcam A-549 MAP3K14 KO	Cancer cell line	Male
CVCL_D7U9	Ubigene A-549 MAP3K14 KO	Cancer cell line	Male
CVCL_D8Q0	Ubigene HCT 116 MAP3K14 KO	Cancer cell line	Male
CVCL_D9JC	Ubigene HEK293 MAP3K14 KO	Transformed cell line	Female
CVCL_E0H7	Ubigene HeLa MAP3K14 KO	Cancer cell line	Female
CVCL_SW63	HAP1 MAP3K14 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.