MAP3K13

Summary

MAP3K13 (mitogen-activated protein kinase kinase kinase 13, HGNC:6852) is a protein-coding gene on chromosome 3q27.2, encoding Mitogen-activated protein kinase kinase kinase 13 (O43283). Activates the JUN N-terminal pathway through activation of the MAP kinase kinase MAP2K7.

The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase contains a dual leucine-zipper motif, and has been shown to form dimers/oligomers through its leucine-zipper motif. This kinase can phosphorylate and activate MAPK8/JNK, MAP2K7/MKK7, which suggests a role in the JNK signaling pathway.

Source: NCBI Gene 9175 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 87 total
• Druggable target: yes — 16 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004721

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6852
Approved symbol	MAP3K13
Name	mitogen-activated protein kinase kinase kinase 13
Location	3q27.2
Locus type	gene with protein product
Status	Approved
Aliases	LZK, MEKK13
Ensembl gene	ENSG00000073803
Ensembl biotype	protein_coding
OMIM	604915
Entrez	9175

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 15 protein_coding, 4 nonsense_mediated_decay, 1 retained_intron

ENST00000265026, ENST00000420577, ENST00000424227, ENST00000428617, ENST00000433092, ENST00000438053, ENST00000438798, ENST00000439882, ENST00000443863, ENST00000446828, ENST00000447637, ENST00000448876, ENST00000454237, ENST00000455188, ENST00000477582, ENST00000901846, ENST00000901847, ENST00000901848, ENST00000901849, ENST00000950641

RefSeq mRNA: 3 — MANE Select: NM_004721 NM_001242314, NM_001242317, NM_004721

CCDS: CCDS3270, CCDS56298

Canonical transcript exons

ENST00000265026 — 14 exons

Exon	Start	End
ENSE00001255068	185363136	185363368
ENSE00001255121	185428497	185429056
ENSE00001936555	185482355	185489094
ENSE00003474830	185480232	185480529
ENSE00003505214	185451287	185451395
ENSE00003531572	185437447	185437630
ENSE00003545192	185466826	185466963
ENSE00003580869	185477326	185477396
ENSE00003590280	185443445	185443636
ENSE00003666743	185447789	185447947
ENSE00003674983	185449900	185450058
ENSE00003675056	185463550	185463659
ENSE00003677699	185472975	185473761
ENSE00003784092	185465747	185465863

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 98.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6982 / max 717.6807, expressed in 1672 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40227	8.9134	1650
40235	1.5236	397
40234	0.2477	55
203052	0.0135	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	98.56	gold quality
caput epididymis	UBERON:0004358	97.60	gold quality
cauda epididymis	UBERON:0004360	97.38	gold quality
sperm	CL:0000019	97.18	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.71	gold quality
lower lobe of lung	UBERON:0008949	96.52	gold quality
mammary duct	UBERON:0001765	96.08	gold quality
buccal mucosa cell	CL:0002336	95.66	gold quality
pons	UBERON:0000988	95.29	gold quality
inferior vagus X ganglion	UBERON:0005363	95.27	gold quality
pylorus	UBERON:0001166	94.80	gold quality
renal medulla	UBERON:0000362	94.79	gold quality
pigmented layer of retina	UBERON:0001782	94.73	gold quality
retina	UBERON:0000966	94.70	gold quality
bronchial epithelial cell	CL:0002328	94.66	gold quality
subthalamic nucleus	UBERON:0001906	94.56	gold quality
ventral tegmental area	UBERON:0002691	94.44	gold quality
superior vestibular nucleus	UBERON:0007227	94.37	gold quality
cardia of stomach	UBERON:0001162	94.22	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.16	gold quality
superficial temporal artery	UBERON:0001614	94.00	gold quality
nipple	UBERON:0002030	93.93	gold quality
islet of Langerhans	UBERON:0000006	93.89	gold quality
oral cavity	UBERON:0000167	93.89	gold quality
adult organism	UBERON:0007023	93.81	gold quality
mammalian vulva	UBERON:0000997	93.33	gold quality
superior surface of tongue	UBERON:0007371	93.23	gold quality
pharyngeal mucosa	UBERON:0000355	93.18	gold quality
male germ cell	CL:0000015	93.08	gold quality
epithelium of mammary gland	UBERON:0003244	92.96	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	20.64
E-CURD-46	yes	16.74
E-HCAD-5	no	2.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TCF3

miRNA regulators (miRDB)

264 targeting MAP3K13, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
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-126-5P	100.00	72.71	3180
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-5696	99.98	72.36	4487

Literature-anchored findings (GeneRIF, showing 5)

• Chromosomal localization studies involving FISH mapping demonstrated that the human LZK gene is located at 3q27. (PMID:12186766)
• Data indicate that miR-206’s effect on Myc was mediated through MAP3K13. (PMID:26918941)
• LZK cooperates with DLK to promote retinal ganglion cell death in response to axon injury. (PMID:28641113)
• The MAP3K13-TRIM25-FBXW7alpha axis affects c-Myc protein stability and tumor development. (PMID:31186535)
• Clinical significance of mitogen-activated protein kinase kinase kinases in hepatitis B virus -related hepatocellular carcinoma and underlying mechanism exploration. (PMID:35311629)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	MAP3K13	ENSDARG00000009493
mus_musculus	Map3k13	ENSMUSG00000033618
rattus_norvegicus	Map3k13	ENSRNOG00000025423

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), 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 13 — O43283 (reviewed: O43283)

Alternative names: Leucine zipper-bearing kinase, Mixed lineage kinase

All UniProt accessions (6): O43283, C9IYH2, C9J4W2, C9JP65, F8WF41, H7C459

UniProt curated annotations — full annotation on UniProt →

Function. Activates the JUN N-terminal pathway through activation of the MAP kinase kinase MAP2K7. Acts synergistically with PRDX3 to regulate the activation of NF-kappa-B in the cytosol. This activation is kinase-dependent and involves activating the IKK complex, the IKBKB-containing complex that phosphorylates inhibitors of NF-kappa-B.

Subunit / interactions. Homodimer; forms dimers through the leucine-zipper motif. Interacts with the C-terminus of MAPK8IP1 through the kinase catalytic domain. Binds PRDX3. Associates with the IKK complex through the kinase domain.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Expressed in the adult brain, liver, placenta and pancreas, with expression strongest in the pancreas.

Post-translational modifications. Autophosphorylated on serine and threonine residues.

Activity regulation. Activated by autophosphorylation and homodimerization.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

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

Isoforms (5)

UniProt ID	Names	Canonical?
O43283-1	1	yes
O43283-3	2
O43283-4	3
O43283-5	4
O43283-6	5

RefSeq proteins (3): NP_001229243, NP_001229246, NP_004712* (*=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
IPR027258	MAPKKK13	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 (43 total): region of interest 10, compositionally biased region 8, splice variant 8, sequence conflict 6, sequence variant 5, binding site 2, chain 1, domain 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43283-F1	57.92	0.25

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): 279 (proton acceptor)

Ligand- & substrate-binding residues (2): 174–182; 195

Mutagenesis-validated functional residues (1):

Position	Phenotype
195	kinase inactive. fails to activate nf-kappa-b.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 283 (showing top): ATF_B, E2F_Q4_01, GOBP_REGULATION_OF_CELL_MATURATION, HNF3ALPHA_Q6, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_NEURON_MATURATION, GOBP_GROWTH, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, AP4_Q6, GOBP_NEUROGENESIS, CREBP1_Q2

GO Biological Process (12): protein phosphorylation (GO:0006468), JNK cascade (GO:0007254), positive regulation of neuron maturation (GO:0014042), positive regulation of axon extension (GO:0045773), protein autophosphorylation (GO:0046777), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), stress-activated MAPK cascade (GO:0051403), positive regulation of neuron projection arborization (GO:0150012), positive regulation of branching morphogenesis of a nerve (GO:1905492), intracellular signal transduction (GO:0035556), regulation of macromolecule metabolic process (GO:0060255), regulation of primary metabolic process (GO:0080090)

GO Molecular Function (16): protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein serine/threonine kinase activator activity (GO:0043539), metal ion binding (GO:0046872), IkappaB kinase complex binding (GO:0106137), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	3
positive regulation of developmental process	2
intracellular anatomical structure	2
regulation of metabolic process	2
protein kinase activity	2
protein serine/threonine kinase activity	2
protein binding	2
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
regulation of neuron maturation	1
neuron maturation	1
positive regulation of cell maturation	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
protein phosphorylation	1
stress-activated protein kinase signaling cascade	1
positive regulation of cell projection organization	1
neuron projection arborization	1
regulation of neuron projection arborization	1
branching morphogenesis of a nerve	1
positive regulation of multicellular organismal process	1
regulation of branching morphogenesis of a nerve	1
signal transduction	1
macromolecule metabolic process	1
primary metabolic process	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
cation binding	1
protein-containing complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1

Protein interactions and networks

STRING

562 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K13	MAPK8IP1	Q9UQF2	899
MAP3K13	MAPK8IP2	Q13387	783
MAP3K13	MAP2K7	O14733	715
MAP3K13	SMAD4	Q13485	694
MAP3K13	JUN	P05412	574
MAP3K13	RIPK3	Q9Y572	546
MAP3K13	RIPK1	Q13546	539
MAP3K13	DVL3	Q92997	505
MAP3K13	SH3RF1	Q7Z6J0	486
MAP3K13	RHOA	P06749	478
MAP3K13	CASP8	Q14790	474
MAP3K13	SHROOM3	Q8TF72	474
MAP3K13	MYCBP2	O75592	458
MAP3K13	DVL2	O14641	426
MAP3K13	FBXO45	P0C2W1	422

IntAct

10 interactions, top by confidence:

A	B	Type	Score
MAP3K13	MAP3K13	psi-mi:“MI:0915”(physical association)	0.400
MAP3K13		psi-mi:“MI:0915”(physical association)	0.400
MAP3K13	GLO1	psi-mi:“MI:0915”(physical association)	0.370
HLA-DRB3	MAP3K13	psi-mi:“MI:0915”(physical association)	0.370
MAP3K13	STAT3	psi-mi:“MI:0915”(physical association)	0.370
MAP3K13		psi-mi:“MI:0914”(association)	0.350
MAP3K13	INPPL1	psi-mi:“MI:0914”(association)	0.350
	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (56): HIST2H2AC (Affinity Capture-MS), INPPL1 (Affinity Capture-MS), KLHL20 (Affinity Capture-MS), TKT (Affinity Capture-MS), RANGAP1 (Affinity Capture-MS), LRRC47 (Affinity Capture-MS), PSMD2 (Affinity Capture-MS), GNL3 (Affinity Capture-MS), SAMHD1 (Affinity Capture-MS), TRIM25 (Affinity Capture-MS), TRIM25 (Affinity Capture-Western), MAP3K13 (Affinity Capture-Western), TRIM25 (Biochemical Activity), PRDX3 (Two-hybrid), PRDX3 (Affinity Capture-Western)

ESM2 similar proteins: A0A0K3AV08, A7J1T0, A7J1T2, A7KAX9, A8X775, A8XU52, A9SY39, B4K6T8, G5EBZ8, G5ECQ3, G5EDE9, G5EEK3, G5EEW9, G5EGK6, O01700, O13839, O17862, O43283, O44757, O45797, O61366, O62090, O95835, P03949, P83510, Q03345, Q09314, Q09446, Q09994, Q11100, Q11181, Q17353, Q21341, Q3LRZ3, Q5R8X7, Q60JJ0, Q60LV7, Q61DP2, Q6E3D4, Q6GPD0

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

2 interactions.

A	Effect	B	Mechanism
MAP3K13	up-regulates	MAP2K7	phosphorylation
MAP3K13	“up-regulates quantity by stabilization”	TRIM25	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3054 predictions. Top by Δscore:

Variant	Effect	Δscore
3:185437598:G:GT	donor_gain	1.0000
3:185437630:AG:A	donor_loss	1.0000
3:185437631:G:GG	donor_gain	1.0000
3:185437631:GTA:G	donor_loss	1.0000
3:185447785:A:AG	acceptor_gain	1.0000
3:185447785:AAAGT:A	acceptor_gain	1.0000
3:185447786:A:G	acceptor_gain	1.0000
3:185447787:A:G	acceptor_gain	1.0000
3:185447788:G:GG	acceptor_gain	1.0000
3:185447788:GT:G	acceptor_gain	1.0000
3:185447948:G:GA	donor_loss	1.0000
3:185447948:G:GG	donor_gain	1.0000
3:185447949:T:G	donor_loss	1.0000
3:185447950:GAGTG:G	donor_loss	1.0000
3:185450056:GTG:G	donor_gain	1.0000
3:185451279:A:AG	acceptor_gain	1.0000
3:185451280:C:G	acceptor_gain	1.0000
3:185451282:TTTA:T	acceptor_loss	1.0000
3:185451285:A:AG	acceptor_gain	1.0000
3:185451285:A:AT	acceptor_loss	1.0000
3:185451286:G:GA	acceptor_gain	1.0000
3:185451286:GGC:G	acceptor_gain	1.0000
3:185451286:GGCA:G	acceptor_gain	1.0000
3:185451392:TCAGG:T	donor_loss	1.0000
3:185451393:CAGG:C	donor_loss	1.0000
3:185451395:GGTA:G	donor_loss	1.0000
3:185451396:G:GG	donor_gain	1.0000
3:185463548:A:AG	acceptor_gain	1.0000
3:185463549:G:GG	acceptor_gain	1.0000
3:185463658:AG:A	donor_loss	1.0000

AlphaMissense

6389 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:185428990:T:C	C137R	1.000
3:185428994:T:C	L138S	1.000
3:185429003:T:A	V141E	1.000
3:185429015:T:A	I145N	1.000
3:185437452:T:A	W161R	1.000
3:185437452:T:C	W161R	1.000
3:185437454:G:C	W161C	1.000
3:185437454:G:T	W161C	1.000
3:185437464:T:C	F165L	1.000
3:185437465:T:C	F165S	1.000
3:185437465:T:G	F165C	1.000
3:185437466:T:A	F165L	1.000
3:185437466:T:G	F165L	1.000
3:185437474:T:A	I168N	1.000
3:185437474:T:C	I168T	1.000
3:185437474:T:G	I168S	1.000
3:185437483:T:A	L171Q	1.000
3:185437483:T:C	L171P	1.000
3:185437488:T:A	W173R	1.000
3:185437488:T:C	W173R	1.000
3:185437489:G:C	W173S	1.000
3:185437490:G:C	W173C	1.000
3:185437490:G:T	W173C	1.000
3:185437492:T:C	L174P	1.000
3:185437494:G:C	G175R	1.000
3:185437494:G:T	G175C	1.000
3:185437495:G:A	G175D	1.000
3:185437495:G:T	G175V	1.000
3:185437497:A:C	S176R	1.000
3:185437499:T:A	S176R	1.000

dbSNP variants (sampled 300 via entrez): RS1000010127 (3:185363242 C>T), RS1000019374 (3:185360639 C>A,T), RS1000032558 (3:185311871 A>G), RS1000038867 (3:185405996 T>G), RS1000062970 (3:185462212 C>T), RS1000069296 (3:185370738 A>G), RS1000082985 (3:185368259 T>A,C), RS1000100987 (3:185347228 A>C,G), RS1000107013 (3:185301512 A>G), RS1000128924 (3:185420733 G>T), RS1000145760 (3:185447836 C>T), RS1000164498 (3:185401074 A>G,T), RS1000172736 (3:185308691 C>T), RS1000178389 (3:185356211 A>G), RS1000187845 (3:185398257 C>A)

Disease associations

OMIM: gene MIM:604915 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001621_10	Airflow obstruction	9.000000e-06
GCST003558_1	Major depressive disorder	5.000000e-11
GCST008403_41	Arterial stiffness index	1.000000e-06
GCST011780_4	Neonatal white matter microstructure	5.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004517	arterial stiffness measurement
EFO:0005674	white matter microstructure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1163124 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

16 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 147,631 (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
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
GNE-3511	Inhibition	9.3	pKi

ChEMBL bioactivities

52 potent at pChembl≥5 of 52 total, top 49 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5286166
8.52	IC50	3	nM	CHEMBL3393333
8.22	IC50	6	nM	CHEMBL5268969
8.22	IC50	6	nM	CHEMBL5271665
8.15	IC50	7	nM	CHEMBL5271972
8.05	IC50	9	nM	CHEMBL5270353
8.00	IC50	10	nM	CHEMBL5287658
7.89	IC50	13	nM	CHEMBL5272522
7.85	IC50	14	nM	GDC-0134
7.80	Kd	16	nM	FORETINIB
7.77	IC50	17	nM	CHEMBL5281494
7.64	IC50	23	nM	CHEMBL5276415
7.54	IC50	29	nM	CHEMBL5277276
7.46	IC50	35	nM	CHEMBL5276337
7.40	IC50	40	nM	CHEMBL5284890
7.36	IC50	44	nM	CHEMBL5288706
7.35	IC50	45	nM	CHEMBL5273015
7.35	IC50	45	nM	CHEMBL5268950
7.35	IC50	45	nM	CHEMBL5283101
7.24	Kd	57	nM	TAE-684
7.21	IC50	61	nM	CHEMBL5278185
7.12	IC50	75	nM	CHEMBL5269484
7.11	IC50	78	nM	CHEMBL5277751
7.02	Kd	95	nM	SUNITINIB
6.96	IC50	111	nM	CHEMBL5278476
6.92	Kd	120	nM	CHEMBL3715238
6.85	Kd	140	nM	NINTEDANIB
6.83	IC50	149	nM	CHEMBL5284496
6.77	Kd	170	nM	DOVITINIB
6.75	Kd	180	nM	TOZASERTIB
6.70	IC50	202	nM	CHEMBL5269792
6.68	Kd	210	nM	CHEMBL1908395
6.68	Kd	210	nM	STAUROSPORINE
6.64	Kd	230	nM	CRIZOTINIB
6.61	IC50	247	nM	CHEMBL5281886
6.47	Kd	340	nM	LESTAURTINIB
6.34	Kd	460	nM	CHEMBL3719135
6.32	Kd	480	nM	BOSUTINIB
6.30	Kd	500	nM	KW-2449
6.27	Kd	540	nM	SU-014813
6.23	Kd	590	nM	FEDRATINIB
6.13	Kd	740	nM	AST-487
6.13	Kd	740	nM	NERATINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.55	Kd	2800	nM	MIDOSTAURIN
5.50	Kd	3200	nM	PHA-665752
5.28	Kd	5300	nM	DASATINIB

PubChem BioAssay actives

49 with measured affinity, of 151 total; 46 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
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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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
2-[[6-(3,3-difluoropyrrolidin-1-yl)-4-[1-(oxetan-3-yl)piperidin-4-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1935988: Inhibition of LZK (unknown origin)	ic50	0.0030	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0060	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0060	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0070	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0090	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	1935988: Inhibition of LZK (unknown origin)	ic50	0.0100	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine	1935988: Inhibition of LZK (unknown origin)	ic50	0.0140	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624965: Binding constant for LZK kinase domain	kd	0.0160	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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
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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0230	uM
5-[2-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-4-pyridinyl]-3-(difluoromethoxy)pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0290	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0350	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0400	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0440	uM
3-(difluoromethoxy)-5-[6-(3,3-difluoropyrrolidin-1-yl)-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0450	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0450	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	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0450	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624965: Binding constant for LZK kinase domain	kd	0.0570	uM
5-[6-cyclopropyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]-3-(difluoromethoxy)pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0610	uM
5-[4-cyclopropyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-pyridinyl]-3-(difluoromethoxy)pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0750	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]pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.0780	uM
Sunitinib	507594: Binding affinity to LZK	kd	0.0950	uM
5-[3-cyclopropyl-5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-3-(difluoromethoxy)pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.1110	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	1491647: Binding affinity to full length wild type human LZK (M1 to W966 residues) expressed in mammalian cells by KINOMEscan assay	kd	0.1200	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624965: Binding constant for LZK kinase domain	kd	0.1400	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-(trifluoromethyl)pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.1490	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	624965: Binding constant for LZK kinase domain	kd	0.1700	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	624965: Binding constant for LZK kinase domain	kd	0.1800	uM
3-(difluoromethoxy)-5-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-6-[(2R)-oxolan-2-yl]pyrimidin-4-yl]pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.2020	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624965: Binding constant for LZK kinase domain	kd	0.2100	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624965: Binding constant for LZK kinase domain	kd	0.2100	uM
Crizotinib	624965: Binding constant for LZK kinase domain	kd	0.2300	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]pyrazin-2-amine	1935990: Inhibition of recombinant N-terminal GST-tagged human LZK (9 to 114 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	0.2470	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507594: Binding affinity to LZK	kd	0.3400	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	1491647: Binding affinity to full length wild type human LZK (M1 to W966 residues) expressed in mammalian cells by KINOMEscan assay	kd	0.4600	uM
Bosutinib	624965: Binding constant for LZK kinase domain	kd	0.4800	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624965: Binding constant for LZK kinase domain	kd	0.5000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624965: Binding constant for LZK kinase domain	kd	0.5400	uM
Fedratinib	624965: Binding constant for LZK kinase domain	kd	0.5900	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624965: Binding constant for LZK kinase domain	kd	0.7400	uM
Neratinib	624965: Binding constant for LZK kinase domain	kd	0.7400	uM
Midostaurin	507594: Binding affinity to LZK	kd	2.8000	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	624965: Binding constant for LZK kinase domain	kd	3.2000	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	624965: Binding constant for LZK kinase domain	kd	5.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Cadmium Chloride	increases expression	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
resorcinol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Glyphosate	decreases expression	1
Ethanol	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation	1
Cannabinoids	affects methylation, increases abundance	1
Copper	affects binding, decreases expression	1
Disulfiram	affects binding, decreases expression	1
Diuron	decreases expression	1
Folic Acid	increases expression, affects cotreatment	1
Quercetin	decreases expression	1
Tretinoin	increases expression	1
Tunicamycin	decreases expression	1
Valproic Acid	increases expression	1
Antirheumatic Agents	affects expression, decreases expression	1

ChEMBL screening assays

75 unique, capped per target: 75 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1166053	Binding	Inhibition of LZK at 1 uM	Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8PZ	Ubigene HCT 116 MAP3K13 KO	Cancer cell line	Male
CVCL_D9JB	Ubigene HEK293 MAP3K13 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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