MAP3K9

Summary

MAP3K9 (mitogen-activated protein kinase kinase kinase 9, HGNC:6861) is a protein-coding gene on chromosome 14q24.2, encoding Mitogen-activated protein kinase kinase kinase 9 (P80192). Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

Enables molecular function activator activity and protein serine/threonine kinase activity. Involved in protein autophosphorylation. Predicted to be located in membrane. Predicted to be active in cytoplasm.

Source: NCBI Gene 4293 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 174 total
• Druggable target: yes — 26 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001284230

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6861
Approved symbol	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Location	14q24.2
Locus type	gene with protein product
Status	Approved
Aliases	PRKE1, MEKK9
Ensembl gene	ENSG00000006432
Ensembl biotype	protein_coding
OMIM	600136
Entrez	4293

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000381250, ENST00000553414, ENST00000554024, ENST00000554146, ENST00000554752, ENST00000555993, ENST00000933970, ENST00000933971

RefSeq mRNA: 4 — MANE Select: NM_001284230 NM_001284230, NM_001284231, NM_001284232, NM_033141

CCDS: CCDS32112, CCDS61485, CCDS61488

Canonical transcript exons

ENST00000554752 — 12 exons

Exon	Start	End
ENSE00000658868	70748829	70749004
ENSE00000807873	70732539	70733342
ENSE00001013682	70734386	70734498
ENSE00001137119	70735961	70736029
ENSE00001137128	70738245	70738398
ENSE00001137138	70740042	70740164
ENSE00001137145	70800667	70801080
ENSE00001229326	70742351	70742591
ENSE00001518024	70808766	70809513
ENSE00001612964	70749933	70750081
ENSE00002597852	70722526	70730864
ENSE00003691777	70761002	70761182

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 92.13.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9660 / max 30.7455, expressed in 752 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143921	1.5485	677
143922	0.4175	248

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.13	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.90	gold quality
esophagus squamous epithelium	UBERON:0006920	91.48	gold quality
epithelium of esophagus	UBERON:0001976	90.27	gold quality
cerebellar vermis	UBERON:0004720	88.85	gold quality
substantia nigra pars compacta	UBERON:0001965	88.58	gold quality
frontal pole	UBERON:0002795	87.56	gold quality
postcentral gyrus	UBERON:0002581	87.45	gold quality
lower esophagus mucosa	UBERON:0035834	87.33	gold quality
amniotic fluid	UBERON:0000173	87.31	gold quality
parietal lobe	UBERON:0001872	87.18	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.16	gold quality
orbitofrontal cortex	UBERON:0004167	86.78	gold quality
middle temporal gyrus	UBERON:0002771	86.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.44	gold quality
paraflocculus	UBERON:0005351	86.31	gold quality
CA1 field of hippocampus	UBERON:0003881	86.08	gold quality
squamous epithelium	UBERON:0006914	86.03	gold quality
superior frontal gyrus	UBERON:0002661	85.88	gold quality
cerebellum	UBERON:0002037	85.49	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.48	gold quality
pons	UBERON:0000988	85.13	gold quality
primary visual cortex	UBERON:0002436	85.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.87	gold quality
cerebellar cortex	UBERON:0002129	84.81	gold quality
cerebellar hemisphere	UBERON:0002245	84.78	gold quality
entorhinal cortex	UBERON:0002728	84.48	gold quality
Brodmann (1909) area 10	UBERON:0013541	84.14	gold quality
occipital lobe	UBERON:0002021	84.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

397 targeting MAP3K9, 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-8485	100.00	77.57	4731
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3185	99.99	68.12	1959
HSA-LET-7A-5P	99.98	72.29	1790

Literature-anchored findings (GeneRIF, showing 11)

• estrogen receptor-alpha transcriptional activity is repressed by the Rho/megakaryoblastic leukemia 1 signaling pathway (PMID:19826002)
• It was found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. (PMID:22197930)
• identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation (PMID:23836671)
• miR148b directly targeted mitogenactivated protein kinase (MAPK) kinase kinase 9 (MAP3K9), an upstream activator of MAPK kinase/cJun Nterminal kinase (JNK) signaling, suppressing the protein but not the mRNA levels. (PMID:26573018)
• There was a negatively relationship between miR-15a and MAP3K9 expression in NP cells. (PMID:28081468)
• Data report that MKL1 was both sufficient and necessary for p65-dependent pro-inflammatory transcriptional program. MKL1 deficiency erased key histone modifications synonymous with transactivation on p65 target promoters. Specifically, MKL1 defined histone H3K4 trimethylation landscape for NF-kappaB dependent transcription. (PMID:28298643)
• The overexpression of MAP3K9 could promote cell viability, migration and invasion rates, EMT process and ability of cloning, miR4905p could target MAP3K9 and further modulate the proliferation, migration, invasion and EMT of pharyngolaryngeal cancer cells. (PMID:31115491)
• MicroRNA-148a regulates the MAPK/ERK signaling pathway and suppresses the development of esophagus squamous cell carcinoma via targeting MAP3K9. (PMID:31378889)
• Elevation of miR-125b-5p is related to improved prognosis in laryngeal squamous cell carcinoma and inhibits the malignancy and glycometabolic disorder by targeting MAP3K9. (PMID:35188403)
• Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9. (PMID:35388129)
• CircSPI1_005 ameliorates osteoarthritis by sponging miR-370-3p to regulate the expression of MAP3K9. (PMID:35978511)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k9	ENSDARG00000013491
mus_musculus	Map3k9	ENSMUSG00000042724
rattus_norvegicus	Map3k9	ENSRNOG00000007271

Paralogs (23): TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), 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 9 — P80192 (reviewed: P80192)

Alternative names: Mixed lineage kinase 1

All UniProt accessions (4): P80192, G3V347, G3V4P9, J3KPI6

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Also plays a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.

Subunit / interactions. Homodimer.

Tissue specificity. Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin.

Post-translational modifications. Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-312 is likely to be the main autophosphorylation site. Autophosphorylation also occurs on Thr-304 and Ser-308.

Disease relevance. May play a role in esophageal cancer susceptibility and/or development.

Activity regulation. Homodimerization via the leucine zipper domains is required for autophosphorylation of multiple sites in the activation loop and subsequent activation. Autophosphorylation at Thr-312 is the key step in activation of MAP3K9/MLK1 and is required for full phosphorylation. Autophosphorylation at Thr-304 and Ser-308 have been shown to be of secondary importance in the activation of MAP3K9/MLK1. CEP-1347 and many indolocarbazole analogs have been shown to act as inhibitors of MAP3K9/MLK1 activity.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P80192-1	1	yes
P80192-4	2

RefSeq proteins (4): NP_001271159, NP_001271160, NP_001271161, NP_149132 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001452	SH3_domain	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016231	MLK1-4	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR035779	MLK1-3_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family

Pfam: PF07714, PF14604

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 (64 total): helix 15, strand 9, compositionally biased region 8, region of interest 7, modified residue 5, mutagenesis site 5, sequence variant 4, sequence conflict 3, domain 2, binding site 2, chain 1, active site 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3DTC	X-RAY DIFFRACTION	2.6
4UY9	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P80192-F1	57.56	0.23

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): 268 (proton acceptor)

Ligand- & substrate-binding residues (2): 150–158; 171

Post-translational modifications (5): 304, 305, 308, 312, 533

Mutagenesis-validated functional residues (5):

Position	Phenotype
171	loss of kinase activity and threonine phosphorylation.
304	reduces threonine phosphorylation. impairs jnk activation.
305	little effect on threonine phosphorylation. mildly impairs jnk activation.
308	impairs jnk activation.
312	loss of threonine phosphorylation. strongly impairs jnk activation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 219 (showing top): TGCACTT_MIR519C_MIR519B_MIR519A, BROWNE_HCMV_INFECTION_24HR_UP, chr14q24, KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_UP, BIOCARTA_MAPK_PATHWAY, GOBP_PROTEIN_AUTOPHOSPHORYLATION, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_DN, GAZIN_EPIGENETIC_SILENCING_BY_KRAS, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_MAP_KINASE_KINASE_KINASE_ACTIVITY, GCACTTT_MIR175P_MIR20A_MIR106A_MIR106B_MIR20B_MIR519D, YOSHIMURA_MAPK8_TARGETS_UP

GO Biological Process (6): protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), signal transduction (GO:0007165), positive regulation of apoptotic process (GO:0043065), protein autophosphorylation (GO:0046777), MAPK cascade (GO:0000165)

GO Molecular Function (14): protein serine/threonine kinase activity (GO:0004674), JUN kinase kinase kinase activity (GO:0004706), MAP kinase kinase activity (GO:0004708), ATP binding (GO:0005524), protein homodimerization activity (GO:0042803), protein serine kinase activity (GO:0106310), molecular function activator activity (GO:0140677), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), MAP kinase kinase kinase activity (GO:0004709), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	3
MAPK cascade	2
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
protein phosphorylation	1
intracellular signaling cassette	1
MAP kinase kinase kinase activity	1
protein serine/threonine/tyrosine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
identical protein binding	1
protein dimerization activity	1
molecular function regulator activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein serine/threonine kinase activity	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1488 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K9	CDC42	P21181	566
MAP3K9	MAPK8	P45983	534
MAP3K9	ARMC10	Q8N2F6	508
MAP3K9	SRF	P11831	496
MAP3K9	BCL2	P10415	446
MAP3K9	MYC	P01106	445
MAP3K9	JUN	P05412	428
MAP3K9	ZNF33A	P17013	387
MAP3K9	MAB21L2	Q9Y586	385
MAP3K9	MRTFA	Q969V6	381
MAP3K9	ARHGAP20	Q9P2F6	377
MAP3K9	MCAM	P43121	373
MAP3K9	SP100	P23497	372
MAP3K9	NEMP1	O14524	369
MAP3K9	MAP3K13	O43283	355

IntAct

36 interactions, top by confidence:

A	B	Type	Score
MAP3K9	YWHAG	psi-mi:“MI:0915”(physical association)	0.670
PRKCA	MAP3K9	psi-mi:“MI:0915”(physical association)	0.560
MAP3K9	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
KAT5	MAP3K9	psi-mi:“MI:0915”(physical association)	0.560
LMO3	MAP3K9	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
NCS1	NMT2	psi-mi:“MI:0914”(association)	0.530
HSP90AB1	MAP3K9	psi-mi:“MI:0915”(physical association)	0.520
YWHAE	MAP3K9	psi-mi:“MI:0915”(physical association)	0.500
MAP3K9	SEPTIN7	psi-mi:“MI:0915”(physical association)	0.400
MAP3K9	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
	MAP3K9	psi-mi:“MI:0915”(physical association)	0.400
SFN	MAP3K9	psi-mi:“MI:0915”(physical association)	0.400
M		psi-mi:“MI:0914”(association)	0.350
MAP3K9	DNAJB6	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): MAP3K9 (Biochemical Activity), MAP3K9 (Affinity Capture-MS), MAP3K9 (Affinity Capture-RNA), SEPT7 (Proximity Label-MS), HIST2H2BE (Proximity Label-MS), MAP3K9 (Proximity Label-MS), MAP3K9 (Affinity Capture-MS), MAP3K9 (Affinity Capture-MS), DNAJB6 (Affinity Capture-MS), AP2A2 (Affinity Capture-MS), AP2A1 (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), CLTB (Affinity Capture-MS), DNAJB1 (Affinity Capture-MS), HPCAL1 (Affinity Capture-MS)

ESM2 similar proteins: A0JNI1, E9Q0S6, O94983, O95402, P80192, Q08AE8, Q1JQA8, Q1LZH7, Q28DG6, Q3B7I8, Q3KPL3, Q3U1V8, Q4VAC9, Q53LP3, Q5BJT1, Q5DU25, Q5HZA4, Q5JU85, Q5M836, Q5PQ30, Q5RBI7, Q5REP3, Q5XG99, Q5ZKK0, Q69YU3, Q6DCC7, Q6DEF4, Q6IPM2, Q6IQA2, Q6P606, Q76G19, Q7TSI1, Q7Z3D4, Q80Y50, Q86UU1, Q8BL43, Q8BY98, Q8C0J6, Q8CC84, Q8IV50

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

1 interactions.

A	Effect	B	Mechanism
MAP3K9	“up-regulates activity”	MAP3K9	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 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
Activation of BAD and translocation to mitochondria	7	266.5×	2e-14
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	235.1×	2e-14
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	235.1×	2e-14
Activation of BH3-only proteins	7	173.8×	2e-13
RHO GTPases activate PKNs	7	111.0×	6e-12
Intrinsic Pathway for Apoptosis	7	102.5×	9e-12
FOXO-mediated transcription	5	84.0×	4e-08
SARS-CoV-1-host interactions	7	61.5×	3e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	79.6×	6e-07
regulation of protein localization	5	44.7×	7e-06
intracellular protein localization	8	36.4×	7e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	154
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2288 predictions. Top by Δscore:

Variant	Effect	Δscore
14:70730870:C:CT	acceptor_gain	1.0000
14:70732534:CTCA:C	donor_loss	1.0000
14:70732535:TCACC:T	donor_loss	1.0000
14:70732536:CA:C	donor_loss	1.0000
14:70732538:C:CT	donor_loss	1.0000
14:70733339:TCCT:T	acceptor_gain	1.0000
14:70733340:CCTC:C	acceptor_gain	1.0000
14:70733341:CT:C	acceptor_gain	1.0000
14:70733343:C:CC	acceptor_gain	1.0000
14:70733351:A:AC	acceptor_gain	1.0000
14:70733351:A:C	acceptor_gain	1.0000
14:70733355:C:CT	acceptor_gain	1.0000
14:70733356:A:T	acceptor_gain	1.0000
14:70733360:G:C	acceptor_gain	1.0000
14:70733360:G:GC	acceptor_gain	1.0000
14:70734385:CCCAT:C	donor_gain	1.0000
14:70734505:C:CT	acceptor_gain	1.0000
14:70740041:CA:C	donor_gain	1.0000
14:70740114:T:TA	donor_gain	1.0000
14:70742346:CTGA:C	donor_loss	1.0000
14:70742347:TGA:T	donor_loss	1.0000
14:70742348:GACCA:G	donor_loss	1.0000
14:70742349:A:AC	donor_gain	1.0000
14:70742350:C:CC	donor_gain	1.0000
14:70742377:T:TA	donor_gain	1.0000
14:70742399:T:TA	donor_gain	1.0000
14:70742409:G:A	donor_gain	1.0000
14:70749930:TACCT:T	donor_loss	1.0000
14:70749931:A:AG	donor_loss	1.0000
14:70749931:ACCTT:A	donor_gain	1.0000

AlphaMissense

7213 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:70740160:G:C	F524L	1.000
14:70740160:G:T	F524L	1.000
14:70740161:A:G	F524S	1.000
14:70740162:A:G	F524L	1.000
14:70742467:A:G	L484P	1.000
14:70742473:C:G	R482P	1.000
14:70742494:C:G	R475P	1.000
14:70742503:A:G	L472P	1.000
14:70742566:A:G	L451P	1.000
14:70750065:A:G	W340R	1.000
14:70750065:A:T	W340R	1.000
14:70761060:A:G	W315R	1.000
14:70761060:A:T	W315R	1.000
14:70761121:A:C	D294E	1.000
14:70761121:A:T	D294E	1.000
14:70761122:T:A	D294V	1.000
14:70761122:T:C	D294G	1.000
14:70761122:T:G	D294A	1.000
14:70761123:C:G	D294H	1.000
14:70800684:T:A	D268V	1.000
14:70800684:T:G	D268A	1.000
14:70800687:C:G	R267P	1.000
14:70800733:C:A	G252W	1.000
14:70800836:G:C	C217W	1.000
14:70800838:A:G	C217R	1.000
14:70800857:A:C	C210W	1.000
14:70800859:A:G	C210R	1.000
14:70800913:C:G	A192P	1.000
14:70800974:T:A	K171N	1.000
14:70800974:T:G	K171N	1.000

dbSNP variants (sampled 300 via entrez): RS1000016470 (14:70739118 A>G), RS1000042102 (14:70727459 G>A), RS1000089562 (14:70764391 C>T), RS1000115009 (14:70782969 C>A,T), RS1000163900 (14:70745802 T>G), RS1000183106 (14:70727648 G>C), RS1000218529 (14:70787566 G>T), RS1000263497 (14:70781081 G>A,C), RS1000274146 (14:70788509 T>C), RS1000291574 (14:70794382 C>T), RS1000302504 (14:70776530 C>T), RS1000331752 (14:70810487 A>G), RS1000365272 (14:70732044 A>G), RS1000381640 (14:70781509 T>C), RS1000459334 (14:70769475 G>T)

Disease associations

OMIM: gene MIM:600136 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000885_6	Response to antipsychotic treatment in schizophrenia (reasoning)	1.000000e-06
GCST007490_21	Anthropometric traits (multi-trait analysis)	6.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004350	reasoning
EFO:0004324	body weights and measures

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2872 (SINGLE PROTEIN), CHEMBL6066127 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

26 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 200,605 (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
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL290352	CEP-1347	3	359
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL1922094	APITOLISIB	2	3,070
CHEMBL3989870	BERZOSERTIB	2	1,265
CHEMBL4116008	CERDULATINIB	2
CHEMBL475251	R-406	2
CHEMBL572878	TOZASERTIB	2
CHEMBL1908394	GSK-461364	1
CHEMBL1908397	KW-2449	1
CHEMBL4439321	ATUVECICLIB	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — MLK subfamily

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

Ligand	Action	Affinity	Parameter
CEP-1347	Inhibition	9.0	pIC50
cerdulatinib	Inhibition	8.3	pIC50
URMC-099	Inhibition	7.72	pIC50
compound 8e [PMID: 24432909]	Inhibition	7.42	pIC50
GNE-3511	Inhibition	7.17	pIC50
P505-15	Inhibition	7.06	pIC50
apitolisib	Inhibition	6.63	pIC50

Binding affinities (BindingDB)

34 measured of 47 human assays (47 total across all organisms); most potent 34 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
BIIB-057	IC50	10.5 nM
3-thia-13,23-diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaene-12,14-dione	IC50	58 nM
methyl (15S,16R,18R)-10,23-bis[(ethylsulfanyl)methyl]-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.1^{15,18}.0^{2,6}.0^{7,27}.0^{8,13}.0^{19,26}.0^{20,25}]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	IC50	64 nM
3-(3-hydroxypropyl)-20-methoxy-3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	87 nM
Indenyl[2,3-c]benzothienyl[2,3-e]isoindol-3-one	IC50	110 nM
3-thia-13-azahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	157 nM
20-(propan-2-yloxy)-3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	159 nM
3-thia-13,23-diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	171 nM
PKC-412	KD	190 nM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.1^{15,18}.0^{2,6}.0^{7,27}.0^{8,13}.0^{19,26}.0^{20,25}]octacosa-1(26),2(6),7(27),8(13),9,11,20(25),21,23-nonaene-16-carboxylate	IC50	260 nM
3-oxa-13,23-diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	270 nM
20-methoxy-3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	274 nM
1H-Indenyl[2,3-c]-1H-indenyl[2,3-e]-3H-isoindol-1-one	IC50	277 nM
6H,14H-Naphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5,7(5H,7H)-dione	IC50	300 nM
3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaene-12,14-dione	IC50	339 nM
3,13-diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	364 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
JMC515680 Compound 4	IC50	724 nM
3,13,23-triazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-12-one	IC50	830 nM
3-(2-hydroxyethyl)-3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	1000 nM
3-(2-hydroxyethyl)-20-(propan-2-yloxy)-3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	1060 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
3-oxa-13,23-diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-12-one	IC50	1110 nM
3-(2-hydroxyethyl)-20-methoxy-3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-14-one	IC50	1270 nM
3-thia-13,23-diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-12-one	IC50	2090 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
3,13-diazahexacyclo[14.7.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tricosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-12-one	IC50	2660 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
3,13-diazahexacyclo[14.8.0.0^{2,10}.0^{4,9}.0^{11,15}.0^{17,22}]tetracosa-1(16),2(10),4(9),5,7,11(15),17(22),18,20-nonaen-12-one	IC50	3450 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

133 potent at pChembl≥5 of 139 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.26	IC50	0.544	nM	STAUROSPORINE
9.03	IC50	0.932	nM	STAUROSPORINE
8.82	IC50	1.52	nM	STAUROSPORINE
8.70	Kd	2	nM	CHEMBL4465866
8.52	Kd	3	nM	CHEMBL4576489
8.46	Kd	3.5	nM	LESTAURTINIB
8.40	IC50	4	nM	CERDULATINIB
8.37	Kd	4.3	nM	R-406
8.00	Kd	10	nM	STAUROSPORINE
7.96	IC50	11	nM	STAUROSPORINE
7.89	IC50	13	nM	CHEMBL4218417
7.85	IC50	14	nM	CHEMBL5397819
7.85	IC50	14	nM	CHEMBL5436267
7.82	IC50	15	nM	CHEMBL289772
7.82	Ki	15	nM	BERZOSERTIB
7.82	IC50	15	nM	CHEMBL5436833
7.82	Kd	15	nM	MIDOSTAURIN
7.82	Kd	15	nM	CGP-52421
7.80	IC50	16	nM	CHEMBL288817
7.80	IC50	16	nM	CHEMBL5417152
7.72	IC50	19	nM	CHEMBL2436978
7.72	IC50	19	nM	CHEMBL277817
7.66	IC50	22	nM	CHEMBL416056
7.66	IC50	22	nM	CHEMBL386636
7.66	IC50	22	nM	CHEMBL5435826
7.66	IC50	22	nM	CHEMBL5416972
7.62	IC50	24	nM	CHEMBL5440213
7.60	IC50	25	nM	CHEMBL5421283
7.58	IC50	26	nM	CHEMBL460990
7.55	IC50	28	nM	CHEMBL288229
7.48	IC50	33	nM	CHEMBL460990
7.47	IC50	34	nM	CHEMBL5403058
7.47	IC50	34	nM	CHEMBL5409050
7.46	IC50	35	nM	REBASTINIB
7.42	IC50	38	nM	CEP-1347
7.37	IC50	43	nM	CHEMBL36891
7.35	IC50	44.3	nM	CHEMBL2151321
7.35	IC50	45	nM	CHEMBL288816
7.35	IC50	44.7	nM	CHEMBL5413518
7.34	IC50	46	nM	CHEMBL374581
7.33	IC50	47	nM	CHEMBL5397520
7.31	IC50	49	nM	CHEMBL517743
7.29	IC50	51	nM	CHEMBL3593777
7.28	IC50	52	nM	CHEMBL4281823
7.22	IC50	60	nM	CHEMBL2177736
7.19	IC50	64	nM	CHEMBL5407648
7.18	IC50	66	nM	CHEMBL492258
7.17	IC50	67.8	nM	CHEMBL3393333
7.17	IC50	68	nM	CHEMBL126545
7.16	IC50	69	nM	CHEMBL357490

PubChem BioAssay actives

151 with measured affinity, of 946 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
(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	1715267: Inhibition of human MLK1 using casein as substrate by [gamma-33P]-ATP assay	ic50	0.0005	uM
methyl (15S,16R,18R)-10,23-bis(ethylsulfanylmethyl)-16-hydroxy-15-methyl-3-oxo-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(13),9,11,20(25),21,23,26-nonaene-16-carboxylate	775350: Inhibition of MLK1 (unknown origin) after 20 mins in presence of [33P]-ATP	ic50	0.0010	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526200: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged MAP3K9 (unknown origin) (110 to 422 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0020	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526200: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged MAP3K9 (unknown origin) (110 to 422 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0030	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	507626: Binding affinity to MLK1	kd	0.0035	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	1993892: Inhibition of MLK1 (unknown origin)	ic50	0.0040	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624706: Binding constant for MLK1 kinase domain	kd	0.0043	uM
3-(2-hydroxyethyl)-7-(propan-2-yloxymethyl)-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17,19,21-nonaen-12-one	1384625: Inhibition of recombinant GST-tagged human MLK1 KD (1 to 500 residues) expressed in baculovirus using myelin basic protein as substrate preincubated for 15 mins measured after 30 mins in presence of [gamma-32P]ATP by scintillation counting	ic50	0.0130	uM
N-[4-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-3-methylphenyl]-2-(dimethylamino)acetamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0140	uM
N-[3-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-2-methylphenyl]-2-morpholin-4-ylacetamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0140	uM
methyl (15S,16R,18R)-16-hydroxy-10,23-bis(hydroxymethyl)-15-methyl-3-oxo-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(13),9,11,20(25),21,23,26-nonaene-16-carboxylate	125159: Inhibition of Mixed lineage kinase 1 (MLK1)	ic50	0.0150	uM
[3-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-4-methylphenyl]-(4-methylpiperazin-1-yl)methanone	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0150	uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-16-oxo-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-4-yl]-N-methylbenzamide	507626: Binding affinity to MLK1	kd	0.0150	uM
3-[3-[4-(methylaminomethyl)phenyl]-1,2-oxazol-5-yl]-5-(4-propan-2-ylsulfonylphenyl)pyrazin-2-amine	1555182: ATP competitive inhibition of human MLK1	ki	0.0150	uM
Midostaurin	435297: Binding constant for MLK1 kinase domain	kd	0.0150	uM
methyl (15S,16R,18R)-16-hydroxy-10,23-bis(methoxymethyl)-15-methyl-3-oxo-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(13),9,11,20(25),21,23,26-nonaene-16-carboxylate	125159: Inhibition of Mixed lineage kinase 1 (MLK1)	ic50	0.0160	uM
N-[3-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-2-methylphenyl]-2-(dimethylamino)acetamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0160	uM
methyl (15S,16R,18R)-10,23-bis(ethoxymethyl)-16-hydroxy-15-methyl-3-oxo-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(13),9,11,20(25),21,23,26-nonaene-16-carboxylate	125159: Inhibition of Mixed lineage kinase 1 (MLK1)	ic50	0.0190	uM
3-(1H-indol-5-yl)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine	775426: Inhibition of MLK1 (unknown origin)	ic50	0.0190	uM
4-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0220	uM
4-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-N-[2-(dimethylamino)ethyl]benzamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0220	uM
3,13-diazahexacyclo[14.8.0.02,10.04,9.011,15.017,22]tetracosa-1(16),2(10),4,6,8,11(15),17,19,21-nonaene-12,14-dione	1797180: Mixed-Lineage Kinase Assays from Article 10.1021/jm051074u: “Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.”	ic50	0.0220	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-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-nonaene-16-carboxylate	1797180: Mixed-Lineage Kinase Assays from Article 10.1021/jm051074u: “Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.”	ic50	0.0220	uM
methyl (15R,16S,18S)-16-hydroxy-15-methyl-3-oxo-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-nonaene-16-carboxylate	277636: Inhibition of GST-MLK1 expressed in baculovirus	ic50	0.0220	uM
3-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-N-[2-(dimethylamino)ethyl]benzamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0240	uM
[4-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-3-methylphenyl]-(4-methylpiperazin-1-yl)methanone	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0250	uM
3-(2-hydroxyethyl)-20-propan-2-yloxy-3,13-diazahexacyclo[14.8.0.02,10.04,9.011,15.017,22]tetracosa-1(16),2(10),4,6,8,11(15),17(22),18,20-nonaen-14-one	1798485: Mixed-Lineage Kinase Assay from Article 10.1021/jm8005838: “Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.”	ic50	0.0260	uM
methyl (15S,16R,18R)-10-(ethylsulfanylmethyl)-16-hydroxy-15-methyl-3-oxo-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(13),9,11,20,22,24,26-nonaene-16-carboxylate	125159: Inhibition of Mixed lineage kinase 1 (MLK1)	ic50	0.0280	uM
3-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-N-[2-(dimethylamino)ethyl]-2-methylbenzamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0340	uM
[3-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]phenyl]-morpholin-4-ylmethanone	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0340	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168218: Inhibition of human wild type MLK1 using RBER-GSK3(14 to 27) as substrate preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.0350	uM
methyl (15S,16R,18R)-23-(ethylsulfanylmethyl)-16-hydroxy-15-methyl-3-oxo-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(25),21,23,26-nonaene-16-carboxylate	125159: Inhibition of Mixed lineage kinase 1 (MLK1)	ic50	0.0430	uM
N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-3-(3-propan-2-yloxy-1H-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine	692421: Inhibition of MLK1	ic50	0.0443	uM
2-[4-[[4-[3-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazin-1-yl]ethanol	1983615: Inhibition of MLK1 (unknown origin)	ic50	0.0447	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-10,23-bis(propan-2-ylsulfanylmethyl)-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(13),9,11,20(25),21,23,26-nonaene-16-carboxylate	125159: Inhibition of Mixed lineage kinase 1 (MLK1)	ic50	0.0450	uM
3,13-diazahexacyclo[14.8.0.02,10.04,9.011,15.017,22]tetracosa-1(16),2(10),4,6,8,11(15),17,19,21-nonaen-12-one	1797180: Mixed-Lineage Kinase Assays from Article 10.1021/jm051074u: “Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.”	ic50	0.0460	uM
[4-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]phenyl]-morpholin-4-ylmethanone	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0470	uM
20-cyclopentyloxy-3-(2-hydroxyethyl)-3,13-diazahexacyclo[14.8.0.02,10.04,9.011,15.017,22]tetracosa-1(16),2(10),4,6,8,11(15),17(22),18,20-nonaen-14-one	1798485: Mixed-Lineage Kinase Assay from Article 10.1021/jm8005838: “Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.”	ic50	0.0490	uM
4-[[(3S,4R)-1-(5-cyano-2-pyridinyl)-3-fluoropiperidin-4-yl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide	1234653: Inhibition of MLK1 (unknown origin)	ic50	0.0510	uM
1-[5-(4-amino-7-ethylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethoxy)phenyl]ethanone	1415189: Inhibition of recombinant human MLK1 (134 to 414 residues) using casein as substrate after 40 mins in presence of [gamma-33P]-ATP by scintillation counting analysis	ic50	0.0520	uM
N-[3-[3-[6-bromo-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]-4-methylphenyl]-2-(4-methylpiperazin-1-yl)acetamide	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.0640	uM
20-propan-2-yloxy-3,13-diazahexacyclo[14.8.0.02,10.04,9.011,15.017,22]tetracosa-1(16),2(10),4,6,8,11(15),17(22),18,20-nonaen-14-one	1798485: Mixed-Lineage Kinase Assay from Article 10.1021/jm8005838: “Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.”	ic50	0.0660	uM
2-[[6-(3,3-difluoropyrrolidin-1-yl)-4-[1-(oxetan-3-yl)piperidin-4-yl]-2-pyridinyl]amino]pyridine-4-carbonitrile	1189387: Inhibition of MLK1 (unknown origin)	ic50	0.0678	uM
3-thia-13,23-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17,19,21-nonaene-12,14-dione	1797180: Mixed-Lineage Kinase Assays from Article 10.1021/jm051074u: “Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.”	ic50	0.0680	uM
3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4,6,8,11(15),17,19,21-nonaen-14-one	1797180: Mixed-Lineage Kinase Assays from Article 10.1021/jm051074u: “Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.”	ic50	0.0690	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-10,23-bis(propylsulfanylmethyl)-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(13),9,11,20(25),21,23,26-nonaene-16-carboxylate	125159: Inhibition of Mixed lineage kinase 1 (MLK1)	ic50	0.0900	uM
3-(3-hydroxypropyl)-20-methoxy-3,13-diazahexacyclo[14.8.0.02,10.04,9.011,15.017,22]tetracosa-1(16),2(10),4,6,8,11(15),17(22),18,20-nonaen-14-one	1798485: Mixed-Lineage Kinase Assay from Article 10.1021/jm8005838: “Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.”	ic50	0.1010	uM
3-(2-hydroxyethyl)-20-methoxy-3,13-diazahexacyclo[14.8.0.02,10.04,9.011,15.017,22]tetracosa-1(16),2(10),4,6,8,11(15),17(22),18,20-nonaen-14-one	1798485: Mixed-Lineage Kinase Assay from Article 10.1021/jm8005838: “Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models.”	ic50	0.1030	uM
3-thia-13,23-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17,19,21-nonaen-12-one	1797180: Mixed-Lineage Kinase Assays from Article 10.1021/jm051074u: “Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.”	ic50	0.1110	uM
[3-[3-[6-chloro-7-[[(3S)-1-ethylsulfonylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]-2,5-dimethylpyrrol-1-yl]phenyl]-morpholin-4-ylmethanone	1984557: Inhibition of MLK1 (unknown origin)	ic50	0.1360	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Quercetin	increases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression	1
Cyclosporine	increases expression	1
Asbestos, Crocidolite	affects expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

353 unique, capped per target: 351 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000436	Binding	Inhibition of GST-fused human MLK1 expressed in CHO cells assessed as MKK4 phosphorylation	Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. — J Med Chem
CHEMBL911985	Functional	Inhibition of MKK4 phosphorylation in MLK1 transfected CHO cells at 1 uM after 1 hr	Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SW77	HAP1 MAP3K9 (-) 1	Cancer cell line	Male
CVCL_SW78	HAP1 MAP3K9 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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