MAP3K12

Summary

MAP3K12 (mitogen-activated protein kinase kinase kinase 12, HGNC:6851) is a protein-coding gene on chromosome 12q13.13, encoding Mitogen-activated protein kinase kinase kinase 12 (Q12852). Part of a non-canonical MAPK signaling pathway.

This gene encodes a member of the serine/threonine protein kinase family. This kinase contains a leucine-zipper domain and is predominately expressed in neuronal cells. The phosphorylation state of this kinase in synaptic terminals was shown to be regulated by membrane depolarization via calcineurin. This kinase forms heterodimers with leucine zipper containing transcription factors, such as cAMP responsive element binding protein (CREB) and MYC, and thus may play a regulatory role in PKA or retinoic acid induced neuronal differentiation. Alternatively spliced transcript variants encoding different proteins have been described.

Source: NCBI Gene 7786 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 92 total
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001193511

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6851
Approved symbol	MAP3K12
Name	mitogen-activated protein kinase kinase kinase 12
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	MUK, DLK, ZPKP1, MEKK12
Ensembl gene	ENSG00000139625
Ensembl biotype	protein_coding
OMIM	600447
Entrez	7786

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 6 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000267079, ENST00000547020, ENST00000547035, ENST00000547151, ENST00000547488, ENST00000547803, ENST00000548565, ENST00000548690, ENST00000551511, ENST00000551895, ENST00000552365, ENST00000936896, ENST00000948711

RefSeq mRNA: 2 — MANE Select: NM_001193511 NM_001193511, NM_006301

CCDS: CCDS55831, CCDS8860

Canonical transcript exons

ENST00000547488 — 14 exons

Exon	Start	End
ENSE00000939230	53486439	53486622
ENSE00000939231	53486056	53486247
ENSE00000939232	53485317	53485475
ENSE00000939233	53485056	53485214
ENSE00000939234	53484257	53484365
ENSE00001059106	53479669	53481280
ENSE00001355955	53499427	53499458
ENSE00002360596	53486947	53487428
ENSE00003459497	53482299	53482369
ENSE00003497965	53483911	53484020
ENSE00003520434	53482565	53483189
ENSE00003637242	53483349	53483486
ENSE00003648195	53481941	53482211
ENSE00003675189	53483607	53483723

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 98.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.2373 / max 108.5483, expressed in 1538 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131244	5.2465	1485
131245	0.9908	613

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	98.53	gold quality
cerebellar hemisphere	UBERON:0002245	98.32	gold quality
cerebellar cortex	UBERON:0002129	98.30	gold quality
cerebellum	UBERON:0002037	97.54	gold quality
mucosa of stomach	UBERON:0001199	96.10	gold quality
right uterine tube	UBERON:0001302	96.07	gold quality
right ovary	UBERON:0002118	95.78	gold quality
right frontal lobe	UBERON:0002810	95.76	gold quality
adenohypophysis	UBERON:0002196	95.49	gold quality
endocervix	UBERON:0000458	95.21	gold quality
cerebellar vermis	UBERON:0004720	94.83	gold quality
body of uterus	UBERON:0009853	94.75	gold quality
left ovary	UBERON:0002119	94.51	gold quality
pituitary gland	UBERON:0000007	94.42	gold quality
stromal cell of endometrium	CL:0002255	94.11	gold quality
pericardium	UBERON:0002407	93.97	gold quality
right coronary artery	UBERON:0001625	93.92	gold quality
ovary	UBERON:0000992	93.24	gold quality
peripheral nervous system	UBERON:0000010	93.18	gold quality
tibial nerve	UBERON:0001323	93.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.94	gold quality
left uterine tube	UBERON:0001303	92.93	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.58	gold quality
lower esophagus	UBERON:0013473	92.54	gold quality
descending thoracic aorta	UBERON:0002345	92.46	gold quality
left coronary artery	UBERON:0001626	92.32	gold quality
cingulate cortex	UBERON:0003027	91.92	gold quality
coronary artery	UBERON:0001621	91.90	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.90	gold quality
sural nerve	UBERON:0015488	91.88	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.94
E-CURD-112	no	2.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI1, SP3

miRNA regulators (miRDB)

76 targeting MAP3K12, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3692-3P	99.98	70.27	2139
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-1468-3P	99.96	72.74	3797
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-130A-3P	99.90	73.31	1861

Literature-anchored findings (GeneRIF, showing 13)

• for the selective expression of ZPK gene, cell-specific negative regulatory element(s) which locate outside of the core promoter region repress the potent basic promoter activity (PMID:14697235)
• ZIPK is positively regulated by phosphorylation within its kinase domain and contains an inhibitory C-terminal domain that controls enzyme activity. (PMID:15611134)
• DLK is a signaling molecule implicated in the regulation of keratinocyte terminal differentiation and cornification (PMID:15695824)
• DAPK-ZIPK-L13a axis forms a unique regulatory module that first represses, then repermits inflammatory gene expression. (PMID:18995835)
• Src-dependent tyrosine phosphorylation recombinant human DLK was important for regulation of its activity. DLK may have a role in PDGF signaling. (PMID:19146952)
• the DLK-ERK signaling pathway may act as a regulator of the interaction that occurs between Hsp27 and the cytoskeleton during the formation of the cornified cell envelope, a process conferring to the skin its crucial barrier function (PMID:19675578)
• The results confirm the significance of apoptosis deregulation in CLL, and suggest a possible relationship between ZIPK expression and the clinical course of the disease. (PMID:21526495)
• these findings indicate that DLK participates in cell proliferation and/or survival, at least in part, by modulating the expression of cell cycle regulatory proteins. (PMID:21893036)
• Data suggest that specific pharmacological inhibition of dual leucine zipper kinase (DLK, MAP3K12) may have therapeutic potential in multiple indications of neuronal degeneration. (PMID:25341110)
• miR-130a inhibited the JNK pathway by targeting MAP3K12, contributing to its anti-apoptotic effect and the maintenance of diabetic endothelial progenitor cell function. (PMID:25999017)
• REVIEW: Regulation of Beta-Cell Function and Mass by the Dual Leucine Zipper Kinase (PMID:27100796)
• LZK cooperates with DLK to promote retinal ganglion cell death in response to axon injury. (PMID:28641113)
• Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress cell proliferation and invasion in prostate cancer by regulating MAP3K12 (PMID:30009782)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k12	ENSDARG00000103651
mus_musculus	Map3k12	ENSMUSG00000023050
rattus_norvegicus	Map3k12	ENSRNOG00000015134
drosophila_melanogaster	wnd	FBGN0036896
caenorhabditis_elegans	dlk-1	WBGENE00001008

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 12 — Q12852 (reviewed: Q12852)

Alternative names: Dual leucine zipper bearing kinase, Leucine-zipper protein kinase, MAPK-upstream kinase, Mixed lineage kinase

All UniProt accessions (3): Q12852, F8VUG4, H3BMF0

UniProt curated annotations — full annotation on UniProt →

Function. Part of a non-canonical MAPK signaling pathway. Activated by APOE, enhances the AP-1-mediated transcription of APP, via a MAP kinase signal transduction pathway composed of MAP2K7 and MAPK1/ERK2 and MAPK3/ERK1. May be an activator of the JNK/SAPK pathway.

Subunit / interactions. Homodimer. Interacts with MBIP.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Highly expressed in brain and kidney.

Post-translational modifications. Autophosphorylated on Ser/Thr. Phosphorylated in cytosol under basal conditions and dephosphorylated when membrane-associated. The activity of MAP3K12 can be regulated through its proteasomal degradation. APOE, through a receptor-mediated mechanism, activates MAP3K12 by preventing its proteasomal degradation.

Domain organisation. Interacts with MBIP through the leucine-zipper motif.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q12852-1	1	yes
Q12852-2	2

RefSeq proteins (2): NP_001180440, NP_006292 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017419	MAP3K12_MAP3K13	Family
IPR027257	MAPKKK12	Family
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family

Pfam: PF07714

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 (55 total): helix 15, compositionally biased region 9, strand 7, region of interest 5, sequence conflict 5, modified residue 4, sequence variant 3, binding site 2, chain 1, domain 1, active site 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
9CDY	X-RAY DIFFRACTION	1.5
5CEN	X-RAY DIFFRACTION	1.7
5CEQ	X-RAY DIFFRACTION	1.91
8OUT	X-RAY DIFFRACTION	1.94
8OUR	X-RAY DIFFRACTION	1.95
5CEP	X-RAY DIFFRACTION	1.99
8OUS	X-RAY DIFFRACTION	2.2
5CEO	X-RAY DIFFRACTION	2.28
9CDX	X-RAY DIFFRACTION	2.38
5VO1	X-RAY DIFFRACTION	2.45
8DEG	X-RAY DIFFRACTION	2.79
5VO2	X-RAY DIFFRACTION	2.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12852-F1	60.80	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): 236 (proton acceptor)

Ligand- & substrate-binding residues (2): 131–139; 152

Post-translational modifications (4): 37, 43, 607, 695

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 177 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, TGCACTT_MIR519C_MIR519B_MIR519A, TTCCGTT_MIR191, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, TTGGGAG_MIR150, GOMF_KINASE_ACTIVATOR_ACTIVITY, ONKEN_UVEAL_MELANOMA_UP, GOBP_JNK_CASCADE, CCTGTGA_MIR513, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, BIOCARTA_MAPK_PATHWAY, GOBP_NEURON_APOPTOTIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS

GO Biological Process (10): protein phosphorylation (GO:0006468), JNK cascade (GO:0007254), intracellular signal transduction (GO:0035556), post-translational protein modification (GO:0043687), positive regulation of DNA-templated transcription (GO:0045893), protein autophosphorylation (GO:0046777), positive regulation of ERK1 and ERK2 cascade (GO:0070374), negative regulation of motor neuron apoptotic process (GO:2000672), regulation of macromolecule metabolic process (GO:0060255), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (12): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein homodimerization activity (GO:0042803), protein serine/threonine kinase activator activity (GO:0043539), 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 (6): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), growth cone (GO:0030426), axon (GO:0030424)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein modification process	2
MAPK cascade	2
intracellular anatomical structure	2
regulation of metabolic process	2
protein kinase activity	2
protein serine/threonine kinase activity	2
phosphorylation	1
signal transduction	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
protein phosphorylation	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
negative regulation of neuron apoptotic process	1
motor neuron apoptotic process	1
regulation of motor neuron apoptotic process	1
macromolecule metabolic process	1
primary metabolic process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
identical protein binding	1
protein dimerization activity	1
protein kinase activator activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
membrane	1
cell periphery	1
site of polarized growth	1
distal axon	1

Protein interactions and networks

STRING

564 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K12	MBIP	Q9NS73	891
MAP3K12	TARS1	P26639	829
MAP3K12	TARS3	A2RTX5	767
MAP3K12	TARS2	Q9BW92	767
MAP3K12	LARS2	Q15031	682
MAP3K12	MAPK8IP1	Q9UQF2	678
MAP3K12	DLK1	P15803	637
MAP3K12	LARS1	Q9P2J5	630
MAP3K12	RIPK1	Q13546	565
MAP3K12	JUN	P05412	553
MAP3K12	RIPK3	Q9Y572	544
MAP3K12	DVL3	Q92997	511
MAP3K12	RPS14	P06366	497
MAP3K12	DVL2	O14641	470
MAP3K12	SHROOM3	Q8TF72	454

IntAct

13 interactions, top by confidence:

A	B	Type	Score
EGFR	AP2A1	psi-mi:“MI:0914”(association)	0.670
EGFR	MAP3K12	psi-mi:“MI:0915”(physical association)	0.620
MAP3K12	EGFR	psi-mi:“MI:0915”(physical association)	0.620
FRA10AC1	MAP3K12	psi-mi:“MI:0915”(physical association)	0.510
MAP3K12	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
MAPK6	MAP3K12	psi-mi:“MI:0915”(physical association)	0.370
MAP3K12	metE	psi-mi:“MI:0915”(physical association)	0.000
TSC22D1	MAP3K12	psi-mi:“MI:0915”(physical association)	0.000
FTL	MAP3K12	psi-mi:“MI:0915”(physical association)	0.000
RGS1	MAP3K12	psi-mi:“MI:0915”(physical association)	0.000
FRA10AC1	MAP3K12	psi-mi:“MI:0915”(physical association)	0.000
RPL18A	MAP3K12	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): MAP3K12 (Affinity Capture-RNA), MAP3K12 (Protein-RNA), MAP3K12 (Two-hybrid), MAP3K12 (Two-hybrid), MAP3K12 (Two-hybrid), MAPK8IP1 (Affinity Capture-Western), MAPK8IP2 (Affinity Capture-Western), MAPK8IP1 (Reconstituted Complex), MAPK8IP2 (Reconstituted Complex), MAP3K12 (Two-hybrid), MAP3K12 (Affinity Capture-Western), MAP2K7 (Biochemical Activity), MAP2K7 (Affinity Capture-Western), FKBPL (Affinity Capture-Western), FKBP4 (Affinity Capture-Western)

ESM2 similar proteins: A2ARS0, A5PJP1, A5PKW4, A6QQ91, C9JTQ0, D3ZG83, F1MUS9, O14512, O14559, O75427, O95996, P0C0T2, P46062, Q02779, Q09019, Q12852, Q18PE0, Q18PE1, Q1LZC5, Q2KI85, Q2TAL5, Q2VPJ9, Q3UMT1, Q53LP3, Q566C8, Q5BJT1, Q5DTT2, Q60700, Q63HR2, Q66L42, Q69YU3, Q6GQX6, Q6NSJ2, Q6NXT1, Q6QNY0, Q7TN12, Q80YF9, Q86YV0, Q8C0J6, Q8C2K5

Diamond homologs: A0A0K3AV08, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, G5EE56, H2KZW3, O01700, O19064, O22558, O43283, O54967, O60674, P00529, P00533, P00534, P00535, P03949, P04412, P06239, P06240, P08069, P08922, P08941, P09760, P09769, P11273, P11362, P13388, P14234, P14616, P14617, P16092, P16591, P18461, P21802, P21803, P21804, P22607

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
SH3RF1	up-regulates	MAP3K12	binding
MAPK8IP1	down-regulates	MAP3K12	binding
MAP3K12	up-regulates	MYL12B	phosphorylation
MAP3K12	“up-regulates activity”	MAP2K4	phosphorylation
MAP3K12	“up-regulates activity”	MAP2K7	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2719 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53482295:TTA:T	donor_loss	1.0000
12:53482298:C:CT	donor_loss	1.0000
12:53482298:CCT:C	donor_gain	1.0000
12:53482365:CGTTT:C	acceptor_gain	1.0000
12:53482368:TT:T	acceptor_gain	1.0000
12:53482979:T:TA	donor_gain	1.0000
12:53483043:C:A	donor_gain	1.0000
12:53483601:GGTTA:G	donor_loss	1.0000
12:53483602:GTTAC:G	donor_loss	1.0000
12:53483603:TTAC:T	donor_loss	1.0000
12:53483605:A:C	donor_loss	1.0000
12:53483606:C:CT	donor_loss	1.0000
12:53483622:T:A	donor_gain	1.0000
12:53483719:CGTGT:C	acceptor_gain	1.0000
12:53483907:TCAC:T	donor_loss	1.0000
12:53483908:CA:C	donor_loss	1.0000
12:53483909:A:AC	donor_gain	1.0000
12:53483910:C:CC	donor_gain	1.0000
12:53484017:CTGC:C	acceptor_gain	1.0000
12:53484018:TGC:T	acceptor_gain	1.0000
12:53484018:TGCC:T	acceptor_loss	1.0000
12:53484019:GC:G	acceptor_gain	1.0000
12:53484020:CC:C	acceptor_gain	1.0000
12:53484020:CCTA:C	acceptor_loss	1.0000
12:53484021:C:CC	acceptor_gain	1.0000
12:53484028:T:C	acceptor_gain	1.0000
12:53484266:A:AC	donor_gain	1.0000
12:53484267:A:C	donor_gain	1.0000
12:53484276:T:TA	donor_gain	1.0000
12:53484300:G:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000055065 (12:53489920 G>A), RS1000304068 (12:53497057 C>T), RS1000310038 (12:53502657 C>A,G), RS1000619064 (12:53488714 C>A,T), RS1000863261 (12:53502001 GCCC>G), RS1001183394 (12:53485066 G>A), RS1001227149 (12:53495730 G>A,T), RS1001265723 (12:53491676 G>A,C), RS1001353948 (12:53496291 T>C), RS1001356107 (12:53499173 C>A,T), RS1001489907 (12:53498900 C>G,T), RS1001612672 (12:53479326 T>C), RS1001745048 (12:53503420 C>T), RS1001757279 (12:53485548 T>C), RS1001798798 (12:53502996 C>T)

Disease associations

OMIM: gene MIM:600447 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004904_133	Body mass index	1.000000e-08
GCST005956_70	Waist-to-hip ratio adjusted for BMI	4.000000e-13
GCST005957_6	Waist-to-hip ratio adjusted for BMI (age <50)	6.000000e-06
GCST005958_9	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-08
GCST005962_20	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1908389 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 155,449 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1908397	KW-2449	1	622
CHEMBL3732012	GDC-0134	1	62
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — LZK subfamily

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
GNE-8505	Inhibition	9.77	pKi
GNE-3511	Inhibition	9.3	pKi
compound 16d [Tao et al., 2009]	Inhibition	9.0	pIC50
GDC-0134	Inhibition	8.35	pKi
compound 11 [PMID: 26431428]	Inhibition	7.38	pKi
IACS-52825	Inhibition	6.97	pIC50
CEP-1347	Inhibition	6.94	pIC50

Binding affinities (BindingDB)

323 measured of 324 human assays (324 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[4-[6-amino-5-(trifluoromethoxy)-3-pyridinyl]-1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2-methylpropan-1-ol	KD	0.11 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
(2-methoxy-4-methylphenyl)-[3-[6-[(4-methyl-2-pyridinyl)amino]-2-(2-methylpyrrolidin-1-yl)pyrimidin-4-yl]piperidin-1-yl]methanone	KI	0.17 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
1-[4-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2-methylpropan-1-ol	KD	0.29 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
(1S)-1-[4-[6-amino-5-(trifluoromethoxy)-3-pyridinyl]-1-[3-(4-propylpiperazin-1-yl)-1-bicyclo[1.1.1]pentanyl]imidazol-2-yl]-2-methylpropan-1-ol	KD	0.31 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
(1R)-1-[4-[6-amino-5-(trifluoromethoxy)-3-pyridinyl]-1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2,2,2-trifluoroethanol	KD	0.36 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
1-[4-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2,2,2-trifluoroethanol	KD	0.36 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
BDBM301631	KI	0.39 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
6-(1-methylpiperidin-4-yl)-2-[(2R)-2-methylpyrrolidin-1-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	0.4 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
[3-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(4-methyl-2-pyridinyl)amino]pyrimidin-4-yl]piperidin-1-yl]-(2-methoxy-4-methylphenyl)methanone	KI	0.5 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
1-[4-[6-amino-5-(trifluoromethoxy)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2-methylpropan-1-ol	KD	0.62 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
2-(2-methylpyrrolidin-1-yl)-6-piperidin-4-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	0.735 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
(1S)-1-[4-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2,2,2-trifluoroethanol	KD	0.74 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
2-[(2R)-2-methylpyrrolidin-1-yl]-6-piperidin-4-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	0.85 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
N-(4-cyclopropyl-2-pyridinyl)-2-[(2R)-2-methylpyrrolidin-1-yl]-6-piperidin-4-ylpyrimidin-4-amine	KI	0.95 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
1-[2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,6-dimethyl-8,9-dihydropurino[8,9-c][1,4]oxazin-4-yl]azetidine-3-carbonitrile	KI	1.25 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
2-imidazol-1-yl-1-[3-[2-(2-methylpyrrolidin-1-yl)-6-[[4-(trifluoromethyl)-2-pyridinyl]amino]pyrimidin-4-yl]pyrrolidin-1-yl]ethanone	KI	1.59 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
1-[4-[6-amino-5-(trifluoromethoxy)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2,2,2-trifluoroethanol	KD	1.6 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
N,N-dimethyl-2-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,8,9,10-tetrahydropurino[8,9-c][1,4]oxazepin-4-amine	KI	1.64 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
Staurosporine	KD	1.7 nM
(1-methylimidazol-4-yl)-[3-[2-(2-methylpyrrolidin-1-yl)-6-[[4-(trifluoromethyl)-2-pyridinyl]amino]pyrimidin-4-yl]pyrrolidin-1-yl]methanone	KI	1.72 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
4-[3-[2-cyclopropyl-4-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]morpholine	KD	1.9 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
1-[4-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]propan-1-ol	KD	2.1 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
1-[4-[2-[(2R)-2-methylpyrrolidin-1-yl]-6-[[4-(trifluoromethyl)-2-pyridinyl]amino]pyrimidin-4-yl]piperidin-1-yl]ethanone	KI	2.2 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
2-amino-5-[6-(2-azabicyclo[2.1.1]hexan-2-yl)-10,10-dimethyl-11-oxa-1,5,8-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-4-yl]pyridine-3-carbonitrile	KI	2.23 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
(R)-[4-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-cyclopropylmethanol	KD	2.3 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
[4-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-cyclopropylmethanol	KD	2.4 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
2-(3,3-difluoropyrrolidin-1-yl)-6-piperidin-4-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	2.43 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
4-[3-[2-propan-2-yl-4-[1-(1-pyridin-2-ylethyl)pyrrolo[3,2-b]pyridin-6-yl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]morpholine	KD	2.9 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
5-[2-(cyclopropylmethyl)-1-[3-(4-methylpiperazin-1-yl)-1-bicyclo[1.1.1]pentanyl]imidazol-4-yl]-3-(trifluoromethyl)pyridin-2-amine	KD	3.1 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
2-(3,3-difluoropiperidin-1-yl)-6-pyrrolidin-3-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	3.1 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
2-(3,3-difluoropyrrolidin-1-yl)-6-piperidin-4-yl-N-(4-thiophen-2-yl-2-pyridinyl)pyrimidin-4-amine	KI	3.2 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
2-(3,3-difluoropyrrolidin-1-yl)-6-(1-methylpiperidin-4-yl)-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	4.42 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
5-[1-[3-(4-methylpiperazin-1-yl)-1-bicyclo[1.1.1]pentanyl]-2-propan-2-ylimidazol-4-yl]-3-(trifluoromethoxy)pyridin-2-amine	KD	4.5 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
2-pyrrolidin-1-yl-6-pyrrolidin-3-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	4.8 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
4-(2-azabicyclo[2.1.1]hexan-2-yl)-6,6-dimethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8,9-dihydropurino[8,9-c][1,4]oxazine	KI	4.92 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
2-(3,3-difluoropyrrolidin-1-yl)-6-[1-(1H-pyrazol-4-ylmethyl)pyrrolidin-3-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	4.92 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
5-[6,6-dimethyl-4-(2-oxa-7-azaspiro[3.4]octan-7-yl)-8,9-dihydropurino[8,9-c][1,4]oxazin-2-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile	KI	4.97 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
[4-[6-amino-5-(trifluoromethoxy)-3-pyridinyl]-1-(1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-cyclopropylmethanol	KD	5.1 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
2-(1-methylpyrazol-4-yl)-6-[1-(oxan-4-ylmethyl)pyrrolidin-3-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	KI	5.21 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
4-cyclopropyl-6,6-dimethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8,9-dihydropurino[8,9-c][1,4]oxazine	KI	5.48 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
1-[2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,6-dimethyl-8,9-dihydropurino[8,9-c][1,4]oxazin-4-yl]azetidin-3-ol	KI	5.91 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
5-[6-(2-azabicyclo[2.1.1]hexan-2-yl)-10,10-dimethyl-11-oxa-1,5,8-triazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraen-4-yl]-3-(trifluoromethyl)pyridin-2-amine	KI	5.98 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
5-[2-(2-methylpropyl)-1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)imidazol-4-yl]-3-(trifluoromethyl)pyridin-2-amine	KD	6 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
1-methyl-4-[2-(2-methylpyrrolidin-1-yl)-6-[[4-(trifluoromethyl)-2-pyridinyl]amino]pyrimidin-4-yl]piperidin-2-one	KI	6.12 nM	US-9868720: C-linked heterocycloaklyl substituted pyrimidines and their uses
5-[1-[3-[bis(2-methoxyethyl)amino]-1-bicyclo[1.1.1]pentanyl]-2-cyclopropylimidazol-4-yl]-3-(trifluoromethoxy)pyridin-2-amine	KD	6.4 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
4-(3-methoxyazetidin-1-yl)-2-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,8,9,10-tetrahydropurino[8,9-c][1,4]oxazepine	KI	6.49 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
5-[1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)-2-(oxolan-2-yl)imidazol-4-yl]-3-(trifluoromethoxy)pyridin-2-amine	KD	6.7 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
1-[6,6-dimethyl-2-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-8,9-dihydropurino[8,9-c][1,4]oxazin-4-yl]azetidin-3-ol	KI	6.79 nM	US-10131675: Tricyclic DLK inhibitors and uses thereof
5-[2-cyclopropyl-1-[3-[2-methoxyethyl(methyl)amino]-1-bicyclo[1.1.1]pentanyl]imidazol-4-yl]-3-(trifluoromethoxy)pyridin-2-amine	KD	6.8 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease
5-[2-cyclopropyl-1-[3-[4-(2-fluoroethyl)piperazin-1-yl]-1-bicyclo[1.1.1]pentanyl]imidazol-4-yl]-3-(trifluoromethoxy)pyridin-2-amine	KD	6.9 nM	US-10093664: Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (DLK) kinase for the treatment of disease

ChEMBL bioactivities

1215 potent at pChembl≥5 of 1215 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	Ki	0.06	nM	CHEMBL3733088
9.96	Kd	0.11	nM	CHEMBL6043592
9.92	Kd	0.12	nM	CHEMBL5413922
9.77	Ki	0.17	nM	CHEMBL3715238
9.77	Ki	0.17	nM	CHEMBL3716226
9.77	Ki	0.17	nM	CHEMBL3355003
9.77	Ki	0.17	nM	CHEMBL5825489
9.70	Ki	0.2	nM	CHEMBL3393337
9.68	Kd	0.21	nM	CHEMBL6057411
9.62	Kd	0.24	nM	CHEMBL6027116
9.54	Kd	0.29	nM	CHEMBL5998309
9.54	Kd	0.29	nM	CHEMBL6007681
9.54	Kd	0.29	nM	CHEMBL5420393
9.52	Kd	0.3	nM	CHEMBL5998309
9.51	Ki	0.31	nM	CHEMBL3729613
9.51	Kd	0.31	nM	CHEMBL5780299
9.44	Kd	0.36	nM	CHEMBL5801301
9.44	Kd	0.36	nM	CHEMBL5739714
9.41	Ki	0.39	nM	CHEMBL5772422
9.40	Ki	0.4	nM	CHEMBL3355005
9.40	Ki	0.4	nM	CHEMBL3732543
9.40	Ki	0.4	nM	CHEMBL5749517
9.32	Ki	0.48	nM	CHEMBL3715325
9.30	Ki	0.5	nM	CHEMBL5776187
9.30	Kd	0.5	nM	CHEMBL5970445
9.29	Ki	0.51	nM	CHEMBL3730823
9.28	Ki	0.52	nM	CHEMBL3731122
9.25	Ki	0.56	nM	CHEMBL3732528
9.24	Ki	0.574	nM	CHEMBL3728902
9.21	Kd	0.62	nM	CHEMBL5419888
9.21	Kd	0.62	nM	CHEMBL5932510
9.17	Ki	0.67	nM	CHEMBL3715788
9.15	Ki	0.7	nM	CHEMBL3393334
9.13	Kd	0.74	nM	CHEMBL6048504
9.13	Ki	0.735	nM	CHEMBL5820177
9.11	Ki	0.77	nM	CHEMBL3733275
9.07	Ki	0.85	nM	CHEMBL5863213
9.05	Ki	0.9	nM	CHEMBL3393329
9.05	Ki	0.9	nM	CHEMBL3728441
9.04	Ki	0.91	nM	CHEMBL3732975
9.04	Ki	0.92	nM	CHEMBL3732447
9.02	Ki	0.95	nM	CHEMBL5837386
9.00	Ki	1	nM	CHEMBL3393340
9.00	Ki	1	nM	CHEMBL3393327
9.00	Ki	1	nM	CHEMBL3717769
9.00	Ki	1	nM	CHEMBL3717104
9.00	Ki	1	nM	CHEMBL3731284
9.00	Ki	1	nM	CHEMBL3730273
9.00	Ki	1	nM	CHEMBL3732360
9.00	Ki	1	nM	CHEMBL3727397

PubChem BioAssay actives

213 with measured affinity, of 301 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
2-[[6-cyclobutyloxy-4-[1-(oxetan-3-yl)piperidin-4-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0002	uM
2-[[6-(3,3-difluoropyrrolidin-1-yl)-4-[1-(oxetan-3-yl)piperidin-4-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0005	uM
2-[[6-(3,3-difluoropyrrolidin-1-yl)-4-[1-(oxetan-3-yl)azetidin-3-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0007	uM
2-[[6-(3,3-difluoropyrrolidin-1-yl)-4-(oxan-4-yl)-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0009	uM
2-[[6-cyclopropyl-4-[1-(oxetan-3-yl)piperidin-4-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0010	uM
1-[4-[2-(3,3-difluoropyrrolidin-1-yl)-6-[[4-(trifluoromethyl)-2-pyridinyl]amino]-4-pyridinyl]piperidin-1-yl]ethanone	1189377: Inhibition of DLK (unknown origin)	ki	0.0010	uM
5-[5-[(1S,5R)-3-(2,2-difluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-propan-2-ylpyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0010	uM
2-(3,3-difluoropyrrolidin-1-yl)-6-piperidin-4-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	1189377: Inhibition of DLK (unknown origin)	ki	0.0020	uM
1-[4-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-(3-morpholin-4-yl-1-bicyclo[1.1.1]pentanyl)imidazol-2-yl]-2-methylpropan-1-ol	1935987: Inhibition of DLK (unknown origin)	ic50	0.0020	uM
ethyl (1S,4S)-5-[4-[5-amino-6-(difluoromethoxy)pyrazin-2-yl]-6-(2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0020	uM
ethyl (1S,4S)-5-[4-[5-amino-6-(difluoromethoxy)pyrazin-2-yl]-6-(3,3-difluoropyrrolidin-1-yl)pyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0020	uM
5-[5-[1-(oxetan-3-yl)piperidin-4-yl]-1-propan-2-ylpyrazol-3-yl]-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0023	uM
5-[1-(cyclopropylmethyl)-5-[(1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethoxy)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0030	uM
5-[1-ethyl-5-[(1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0030	uM
5-[1-(2-methylpropyl)-5-[(1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0030	uM
methyl (1S,4S)-5-[4-[5-amino-6-(difluoromethoxy)pyrazin-2-yl]-6-(2-azabicyclo[2.1.1]hexan-2-yl)-2-pyridinyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0030	uM
ethyl (1S,4S)-5-[4-[5-amino-6-(difluoromethoxy)pyrazin-2-yl]-6-methylsulfanylpyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0030	uM
ethyl (1S,4S)-5-[4-[5-amino-6-(difluoromethoxy)pyrazin-2-yl]-6-cyclopropylpyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0030	uM
5-[5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-propan-2-ylpyrazol-3-yl]-3-(trifluoromethoxy)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0030	uM
[3-[2-methyl-6-[(4-propan-2-yl-2-pyridinyl)amino]pyrimidin-4-yl]piperidin-1-yl]-phenylmethanone	1189377: Inhibition of DLK (unknown origin)	ki	0.0040	uM
1-[(1R,5S)-6-[3-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-propan-2-ylpyrazol-5-yl]-3-azabicyclo[3.1.0]hexan-3-yl]propan-2-ol	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0040	uM
3-(difluoromethoxy)-5-[6-(3,3-difluoropyrrolidin-1-yl)-2-[(1S,4S)-5-(6-methylpyridazin-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-yl]pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0040	uM
3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-4-pyridinyl]pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0040	uM
5-[2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0040	uM
3-methyl-5-[5-[1-(oxetan-3-yl)piperidin-4-yl]-1-propan-2-ylpyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0040	uM
5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0040	uM
2-[[6-(3,3-difluoropyrrolidin-1-yl)-4-(2-hydroxypropan-2-yl)-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0050	uM
5-[5-[(1S,5R)-3-(oxetan-3-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-propan-2-ylpyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0050	uM
2-[[4-(4-cyanooxan-4-yl)-6-(3,3-difluoropyrrolidin-1-yl)-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0050	uM
1-[(1S,5R)-6-[3-[6-amino-5-(trifluoromethyl)-3-pyridinyl]-1-propan-2-ylpyrazol-5-yl]-3-azabicyclo[3.1.0]hexan-3-yl]ethanone	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0060	uM
6-piperidin-3-yl-2-pyrrolidin-1-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	1189377: Inhibition of DLK (unknown origin)	ki	0.0070	uM
2-(3,3-difluoropyrrolidin-1-yl)-6-piperidin-3-yl-N-[4-(trifluoromethyl)-2-pyridinyl]pyrimidin-4-amine	1189377: Inhibition of DLK (unknown origin)	ki	0.0070	uM
5-[5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-propan-2-ylpyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0070	uM
3-methoxy-5-[5-[(1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-propan-2-ylpyrazol-3-yl]pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0070	uM
2-[[6-(azetidin-1-yl)-4-[1-(oxetan-3-yl)piperidin-4-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0080	uM
2-[[6-(3-methoxyazetidin-1-yl)-4-[1-(oxetan-3-yl)piperidin-4-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0080	uM
3-(difluoromethoxy)-5-[5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-propan-2-ylpyrazol-3-yl]pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0080	uM
5-[1-(cyclopentylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0090	uM
5-[5-[(1R,5S)-3-(2-methoxyethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-propan-2-ylpyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0090	uM
3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine	1935987: Inhibition of DLK (unknown origin)	ic50	0.0110	uM
5-[1-(cyclobutylmethyl)-5-[(1S,5R)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0110	uM
3-(difluoromethoxy)-5-[6-(3,3-difluoropyrrolidin-1-yl)-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)pyrimidin-4-yl]pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0120	uM
3-(difluoromethoxy)-5-[6-methylsulfanyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0130	uM
5-[6-(2-azabicyclo[2.1.1]hexan-2-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0130	uM
3-(difluoromethoxy)-5-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-6-[(2S)-oxolan-2-yl]pyrimidin-4-yl]pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0130	uM
2-[[4-(2-cyanopropan-2-yl)-6-(3,3-difluoropyrrolidin-1-yl)-2-pyridinyl]amino]pyridine-4-carbonitrile	1189377: Inhibition of DLK (unknown origin)	ki	0.0140	uM
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-4-pyridinyl]-3-(difluoromethoxy)pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0140	uM
3-chloro-5-[5-[1-(oxetan-3-yl)piperidin-4-yl]-1-propan-2-ylpyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0150	uM
5-[5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine	1491640: Binding affinity to N-terminally GST-tagged wild type human DLK (1 to 520 residues) expressed in sf21 insect cells using N-terminally His-tagged MKK4 K131M as substrate after 60 mins in presence of ATP by TR-FRET assay	ki	0.0160	uM
3-(difluoromethoxy)-5-[6-(3,3-difluoropyrrolidin-1-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrazin-2-amine	1935989: Inhibition of recombinant N-terminal GST-tagged human DLK (9 to 111 residues) expressed in Sf21 cells assessed as reduction in substrate phosphorylation using MKK4 and ATP as substrate incubated for 1.5 hrs by HTRF analysis	ic50	0.0170	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, decreases reaction	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects cotreatment, decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
chlorophyllin	decreases reaction, increases expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Quercetin	decreases expression	1
Smoke	decreases expression	1
Urethane	increases expression	1

ChEMBL screening assays

80 unique, capped per target: 80 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1908459	Binding	Binding constant for DLK kinase domain	Comprehensive analysis of kinase inhibitor selectivity. — Nat Biotechnol

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_B1WI	Abcam HeLa MAP3K12 KO	Cancer cell line	Female
CVCL_D7U8	Ubigene A-549 MAP3K12 KO	Cancer cell line	Male
CVCL_D9JA	Ubigene HEK293 MAP3K12 KO	Transformed cell line	Female
CVCL_SW60	HAP1 MAP3K12 (-) 1	Cancer cell line	Male
CVCL_SW61	HAP1 MAP3K12 (-) 2	Cancer cell line	Male
CVCL_SW62	HAP1 MAP3K12 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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