MAP3K11

Summary

MAP3K11 (mitogen-activated protein kinase kinase kinase 11, HGNC:6850) is a protein-coding gene on chromosome 11q13.1, encoding Mitogen-activated protein kinase kinase kinase 11 (Q16584). Activates the JUN N-terminal pathway.

The protein encoded by this gene is a member of the serine/threonine kinase family. This kinase contains a SH3 domain and a leucine zipper-basic motif. This kinase preferentially activates MAPK8/JNK kinase, and functions as a positive regulator of JNK signaling pathway. This kinase can directly phosphorylate, and activates IkappaB kinase alpha and beta, and is found to be involved in the transcription activity of NF-kappaB mediated by Rho family GTPases and CDC42.

Source: NCBI Gene 4296 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 127 total — 1 likely-pathogenic
• Druggable target: yes — 42 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002419

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6850
Approved symbol	MAP3K11
Name	mitogen-activated protein kinase kinase kinase 11
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	SPRK, MEKK11
Ensembl gene	ENSG00000173327
Ensembl biotype	protein_coding
OMIM	600050
Entrez	4296

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 6 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000309100, ENST00000524848, ENST00000524856, ENST00000526293, ENST00000526647, ENST00000527304, ENST00000529839, ENST00000530153, ENST00000530949, ENST00000532507, ENST00000533032, ENST00000534110, ENST00000534432, ENST00000850884, ENST00000866052, ENST00000941368

RefSeq mRNA: 1 — MANE Select: NM_002419 NM_002419

CCDS: CCDS8107

Canonical transcript exons

ENST00000309100 — 10 exons

Exon	Start	End
ENSE00001191629	65597757	65598628
ENSE00001191667	65607641	65607816
ENSE00001191673	65607922	65608070
ENSE00001191685	65613018	65614221
ENSE00003462408	65607270	65607513
ENSE00003571594	65608268	65608448
ENSE00003579304	65599394	65599768
ENSE00003592474	65605761	65605852
ENSE00003634632	65605946	65606081
ENSE00003691098	65606691	65606804

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 96.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.9321 / max 201.3321, expressed in 1769 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120653	12.4198	1765
120652	0.2578	132
120651	0.2544	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	96.60	gold quality
granulocyte	CL:0000094	96.31	gold quality
tibial nerve	UBERON:0001323	95.93	gold quality
apex of heart	UBERON:0002098	95.49	gold quality
mucosa of transverse colon	UBERON:0004991	95.27	gold quality
monocyte	CL:0000576	95.26	gold quality
right lobe of liver	UBERON:0001114	95.26	gold quality
mononuclear cell	CL:0000842	94.93	gold quality
leukocyte	CL:0000738	94.92	gold quality
right lung	UBERON:0002167	94.82	gold quality
spleen	UBERON:0002106	94.49	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.04	gold quality
upper lobe of left lung	UBERON:0008952	93.63	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.58	gold quality
omental fat pad	UBERON:0010414	93.08	gold quality
peritoneum	UBERON:0002358	93.01	gold quality
lower esophagus mucosa	UBERON:0035834	92.97	gold quality
ileal mucosa	UBERON:0000331	92.88	gold quality
endometrium epithelium	UBERON:0004811	92.88	gold quality
upper lobe of lung	UBERON:0008948	92.74	gold quality
transverse colon	UBERON:0001157	92.48	gold quality
left uterine tube	UBERON:0001303	92.48	gold quality
small intestine	UBERON:0002108	92.47	gold quality
spinal cord	UBERON:0002240	92.44	gold quality
blood	UBERON:0000178	92.40	gold quality
metanephros cortex	UBERON:0010533	92.33	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.25	gold quality
body of stomach	UBERON:0001161	91.74	gold quality
right lobe of thyroid gland	UBERON:0001119	91.73	gold quality
middle frontal gyrus	UBERON:0002702	91.70	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.20
E-MTAB-7303	no	555.40
E-MTAB-7249	no	32.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, NFKB, PAX1, TP53

miRNA regulators (miRDB)

53 targeting MAP3K11, 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-7152-3P	99.97	67.47	849
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844

Literature-anchored findings (GeneRIF, showing 40)

• MLK3 may be a negative regulator of the growth-promoting and transforming properties of Rac1 (PMID:11713255)
• Twelve in vivo MLK3 phosphorylation sites have been identified. (PMID:11969422)
• negative regulation by protein kinase B leads to cell survival (PMID:12458207)
• ceramide and TNF-alpha are agonists (PMID:12504027)
• MLK3 is phosphorylated by Akt2, which results in the disassembly of the JNK complex bound to POSH and down-regulation of the JNK signaling pathway (PMID:14504284)
• MLK3 signaling requires Hsp90/p50cdc37 (PMID:15001580)
• These observations support a role for mixed lineage kinases, including MLK3, in the TGF-beta1-induced cell death mechanism. (PMID:15069087)
• MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. (PMID:15258589)
• The MLK3 might be a unique target to selectively inhibit transformed cell proliferation by disrupting mitotic spindle formation resulting in mitotic arrest. (PMID:15923109)
• Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3 (PMID:16253996)
• Merlin and MLK3 can interact in situ and merlin can disrupt the interactions between B-Raf and Raf-1 or those between MLK3 and either B-Raf or Raf-1. (PMID:16537381)
• JNK-mediated feedback phosphorylation of MLK3 regulates its activation and deactivation states by cycling between Triton-soluble and Triton-insoluble forms (PMID:16687404)
• MLK2 and -3 are required for activation of JNK and p38 by ectopically expressed GCK (PMID:17584736)
• a direct link between GSK-3beta and MLK3 activation in a neuronal cell death pathway and identify MLK3 as a direct downstream target of GSK-3beta. (PMID:17711861)
• p38 MAPK inhibitors SB202190 and SB203580 activated JNK via MLK-3/MKK7 pathway. (PMID:18222647)
• findings demonstrate a scaffolding role for MLK3 in controlling the extent of Rho activation that modulates cell migration (PMID:18851832)
• K48-linked ubiquitination directs Mixed lineage kinase 3 for proteosomal degradation while K63-linked ubiquitination is important for Mixed lineage kinase 3 kinase activity. (PMID:19586614)
• MLK3 functions to limit IKK activity, and depleting MLK3 helps protect cells from etoposide-induced cell death through activation of IKK-dependent signaling. (PMID:19782705)
• MLK3 mutations is associated with the mismatch repair deficiency in gastrointestinal cancer. (PMID:19955118)
• Estradiol inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER(+) breast cancer cells. (PMID:20145118)
• Studies indicate that the MLK3/JNK1 axis mediates G17-induced gastric cancer cell migration, which can be targeted for designing novel therapeutic strategies for treating gastric malignancies. (PMID:20150185)
• Novel proteolytic processing of MLK3 may negatively control MLK3 signalling to JNK. (PMID:20158498)
• MLK3 is critical for breast cancer cell migration and promotes cell transformation. (PMID:20514022)
• These results establish merlin as a potent inhibitor of mixed lineage kinase 3, extracellular signal-regulated kinase, and c-jun N-terminal kinase activation in cancer. (PMID:20890305)
• co-expression of MLK3 and beta-catenin resulted in significant G(2)/M arrest. (PMID:21880738)
• Mechanism of MAP kinase activation by TNF requires Src-dependent activation of Vav, activation of Rac/Cdc42, and the engagement of the Rac/Cdc42 interaction site on MLK3. (PMID:21979919)
• Data suggest that MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development. (PMID:22139075)
• Data show that HBx can induce HepG2 cell apoptosis via a novel active MLK3-MKK7-JNKs signaling module to upregulate FasL protein expression. (PMID:22509080)
• These findings collectively suggest that the MLK3-Pin1 signaling cascade plays a critical role in regulating the cell cycle, centrosome numbers, and oncogenesis. (PMID:22566623)
• The findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. (PMID:22652451)
• Findings suggest that the MLK3-JNK-paxillin signaling axis may represent a potential prognostic marker in breast cancer metastasis. (PMID:22700880)
• High MAP3K11 expression is associated with prostate cancer. (PMID:22761715)
• Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic beta cell death (PMID:23172226)
• NS5A targets MLK3 with multiple downstream consequences for both apoptosis and K(+) homeostasis. (PMID:23857585)
• CTGF acting through Rac1 activates the MLK3/JNK signaling pathway, which in turn initiates AP-1 activation and recruitment of c-Jun and c-Fos to the collagen I promoter and ultimately induces collagen I expression in human lung fibroblasts (PMID:23906792)
• Data indicate URMC-099 as an orally bioavailable, potent mixed lineage kinase 3 MLK3 inhibitor. (PMID:24044867)
• Signaling pathways associated with the Pro252His mutation in MLK3 are located in the kinase domain which is an important domain for the regulation of downstream signaling pathways. (PMID:24628919)
• MLK3 is a critical factor controlling the activity of kinase networks that control the cellular responses to different concentrations of reactive oxygen species. (PMID:24894995)
• CHIP modulates MLK3 protein levels in response to Geldanamycin and stress stimuli, and CHIP-dependent regulation of MLK3 is required for suppression of SKOV3 ovarian cancer cell invasion. (PMID:24912674)
• MLK3 serves as a common upstream kinase of AMPK and JNK and functions as a direct upstream kinase for AMPK independent of LKB1 (PMID:25874865)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	MAP3K11	ENSDARG00000091521
mus_musculus	Map3k11	ENSMUSG00000004054
rattus_norvegicus	Map3k11	ENSRNOG00000020773

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), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 11 — Q16584 (reviewed: Q16584)

Alternative names: Mixed lineage kinase 3, Src-homology 3 domain-containing proline-rich kinase

All UniProt accessions (5): E9PID4, E9PLB1, Q16584, E9PRQ2, H0YCF5

UniProt curated annotations — full annotation on UniProt →

Function. Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.

Subunit / interactions. Homodimer; undergoes dimerization during activation. Interacts with MAP2K4/MKK4. Interacts with MAP2K7/MKK7. Found in a complex with SH3RF1, RAC1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Expressed in a wide variety of normal and neoplastic tissues including fetal lung, liver, heart and kidney, and adult lung, liver, heart, kidney, placenta, skeletal muscle, pancreas and brain.

Post-translational modifications. Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-277 is likely to be the main autophosphorylation site. Phosphorylation of Ser-555 and Ser-556 is induced by CDC42.

Activity regulation. Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q16584-1	1	yes
Q16584-2	2

RefSeq proteins (1): NP_002410* (*=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 (62 total): modified residue 23, mutagenesis site 8, compositionally biased region 7, region of interest 5, strand 5, sequence variant 3, domain 2, binding site 2, sequence conflict 2, helix 2, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5K26	X-RAY DIFFRACTION	1.2
5K28	X-RAY DIFFRACTION	1.5
6AQB	X-RAY DIFFRACTION	1.5
6CQ7	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16584-F1	63.79	0.26

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): 241 (proton acceptor)

Ligand- & substrate-binding residues (2): 123–131; 144

Post-translational modifications (23): 11, 35, 277, 281, 394, 507, 524, 548, 555, 556, 654, 693, 705, 708, 724, 727, 740, 748, 758, 770 …

Mutagenesis-validated functional residues (8):

Position	Phenotype
144	greatly reduced autophosphorylation activity.
144	loss of kinase activity. prevents activation of sapk and mapk14.
164	greatly reduced autophosphorylation activity.
277	severely reduced autophosphorylation activity. prevents phosphorylation of sapk and mapk14.
277	no effect on sapk activation.
278	no effect on autophosphorylation activity or activation of sapk and mapk14.
281	reduced autophosphorylation activity. reduced activation of sapk and mapk14.
281	no effect on sapk activation.

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-5673000	RAF activation
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013424	RHOV GTPase cycle
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-194315	Signaling by Rho GTPases
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802949	Signaling by RAS mutants
R-HSA-6802957	Oncogenic MAPK signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 272 (showing top): GOBP_REGULATION_OF_PHOSPHORYLATION, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_CELL_CYCLE_PHASE_TRANSITION, MORF_HDAC1, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOMF_GTPASE_BINDING, CACCAGC_MIR138, GGGTGGRR_PAX4_03, chr11q13, GOCC_MICROTUBULE_ORGANIZING_CENTER, SP1_Q2_01, COUP_01, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (10): MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), microtubule-based process (GO:0007017), JNK cascade (GO:0007254), positive regulation of JUN kinase activity (GO:0043507), positive regulation of neuron apoptotic process (GO:0043525), cell cycle G1/S phase transition (GO:0044843), positive regulation of JNK cascade (GO:0046330), protein autophosphorylation (GO:0046777), positive regulation of apoptotic process (GO:0043065)

GO Molecular Function (16): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), JUN kinase kinase kinase activity (GO:0004706), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), small GTPase binding (GO:0031267), mitogen-activated protein kinase kinase binding (GO:0031434), mitogen-activated protein kinase kinase kinase binding (GO:0031435), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), microtubule (GO:0005874), membrane (GO:0016020), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Oncogenic MAPK signaling	3
RHO GTPase cycle	3
Signal Transduction	2
RAF/MAP kinase cascade	1
Signaling by RAS mutants	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Disease	1
MAPK1/MAPK3 signaling	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	3
cellular anatomical structure	3
MAPK cascade	2
protein kinase binding	2
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
cellular process	1
JUN kinase activity	1
positive regulation of MAP kinase activity	1
regulation of JUN kinase activity	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
cell cycle phase transition	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
protein phosphorylation	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
MAP kinase kinase kinase activity	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
GTPase binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
centriole	1

Protein interactions and networks

STRING

2324 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K11	MAPK8IP1	Q9UQF2	858
MAP3K11	MAPK8IP2	Q13387	807
MAP3K11	FOSL1	P15407	802
MAP3K11	FTH1	P02794	785
MAP3K11	PYGM	P11217	775
MAP3K11	CAPN1	P07384	771
MAP3K11	AHNAK	Q09666	769
MAP3K11	FKBP2	P26885	768
MAP3K11	COX8A	P10176	767
MAP3K11	PLCB3	Q01970	767
MAP3K11	SF1	Q15637	767
MAP3K11	ROM1	Q03395	765
MAP3K11	CHRM1	P11229	764
MAP3K11	SCGB1A1	P11684	763
MAP3K11	RELA	Q04206	711

IntAct

44 interactions, top by confidence:

A	B	Type	Score
MAP3K11	NF2	psi-mi:“MI:0915”(physical association)	0.650
NF2	MAP3K11	psi-mi:“MI:0407”(direct interaction)	0.650
MAP3K11	NF2	psi-mi:“MI:0217”(phosphorylation reaction)	0.650
MAP3K11		psi-mi:“MI:0915”(physical association)	0.610
	MAP3K11	psi-mi:“MI:0915”(physical association)	0.610
	MAP3K11	psi-mi:“MI:0403”(colocalization)	0.610
MAP3K11		psi-mi:“MI:0403”(colocalization)	0.610
MAP3K11	E6	psi-mi:“MI:0915”(physical association)	0.550
MAP3K11	CDC42	psi-mi:“MI:0915”(physical association)	0.540
MAP3K11	CDC42	psi-mi:“MI:2364”(proximity)	0.540
MAP3K11	Map4k1	psi-mi:“MI:0915”(physical association)	0.510
Map4k1	MAP3K11	psi-mi:“MI:0915”(physical association)	0.510
MAPK8	MAP2K7	psi-mi:“MI:0914”(association)	0.480
PIK3R1	MAP2K7	psi-mi:“MI:0914”(association)	0.460
MAP3K11	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
GSK3A	MAP3K11	psi-mi:“MI:0915”(physical association)	0.400
MAP4K2	MAP3K11	psi-mi:“MI:0915”(physical association)	0.400
Grik2	MAP3K11	psi-mi:“MI:0915”(physical association)	0.400
MAP3K11	Mapk8ip1	psi-mi:“MI:0915”(physical association)	0.400
MAP3K11	EPS8	psi-mi:“MI:0915”(physical association)	0.370
MAP3K11	PIN1	psi-mi:“MI:0915”(physical association)	0.370
SPG11	MAP3K11	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (89): MAP3K11 (Two-hybrid), MAP3K11 (Co-localization), KIAA1804 (Reconstituted Complex), KIAA1804 (Affinity Capture-Western), MAP3K11 (Affinity Capture-MS), MAP3K11 (Reconstituted Complex), MAP3K11 (Affinity Capture-Western), MAP3K11 (Co-fractionation), MAP3K11 (Two-hybrid), KIF17 (Two-hybrid), KIF3A (Two-hybrid), KIFAP3 (Two-hybrid), KIF3B (Two-hybrid), MAPK8IP1 (Affinity Capture-Western), MAPK8IP2 (Affinity Capture-Western)

ESM2 similar proteins: A0JPN4, A1YF56, A2A288, A2A9T0, A2AEV7, A6QQJ8, A7MCY6, A8MVW0, D3ZG83, D3ZZN9, O09039, O15037, O75427, O94983, O95382, O95947, P0C5W1, P98077, Q02779, Q16584, Q2M3V2, Q53LP3, Q5D1E7, Q5D1E8, Q66HA1, Q66K74, Q66L42, Q6DG50, Q6ZUM4, Q6ZW31, Q76KP1, Q7T0L4, Q7TSG2, Q80XI6, Q80Y50, Q8BIY3, Q8BLS7, Q8K120, Q8K1S6, Q8R5G7

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

26 interactions.

A	Effect	B	Mechanism
MAP3K11	up-regulates	MAP2K4	phosphorylation
MAPK14	down-regulates	MAP3K11	phosphorylation
MAP3K11	up-regulates	PIN1	phosphorylation
AKT1	down-regulates	MAP3K11	phosphorylation
GSK3B	“up-regulates activity”	MAP3K11	phosphorylation
MAP4K4	“up-regulates activity”	MAP3K11	phosphorylation
MAP3K11	“up-regulates activity”	GOLGA3	phosphorylation
MAP3K11	“up-regulates activity”	PAK1	phosphorylation
MAP3K11	“up-regulates activity”	MAP2K1	phosphorylation
MAP3K11	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K11	up-regulates	MAPK8
MAP3K11	“up-regulates activity”	MAP2K4	phosphorylation
MAP3K11	up-regulates	MAPK9
MAPK8IP3	up-regulates	MAP3K11	binding
MAP3K11	up-regulates	MAP3K11	phosphorylation
MAP4K1	up-regulates	MAP3K11	phosphorylation
AKT	down-regulates	MAP3K11	phosphorylation
SH3RF1	up-regulates	MAP3K11	binding
CDK1	“down-regulates activity”	MAP3K11	phosphorylation
CDK2	“up-regulates activity”	MAP3K11	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	5	16.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	113
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
982194	NM_002419.4(MAP3K11):c.847G>A (p.Ala283Thr)	Likely pathogenic

SpliceAI

1825 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65605756:CTCA:C	donor_loss	1.0000
11:65605757:TCA:T	donor_loss	1.0000
11:65605758:CACCA:C	donor_loss	1.0000
11:65605759:A:AT	donor_loss	1.0000
11:65605760:C:CA	donor_loss	1.0000
11:65605848:TTCTC:T	acceptor_gain	1.0000
11:65605850:CTC:C	acceptor_gain	1.0000
11:65605856:G:GC	acceptor_gain	1.0000
11:65605859:A:AC	acceptor_gain	1.0000
11:65605859:A:C	acceptor_gain	1.0000
11:65605942:TCA:T	donor_loss	1.0000
11:65605943:CACCT:C	donor_loss	1.0000
11:65605944:A:AC	donor_gain	1.0000
11:65605944:A:AT	donor_loss	1.0000
11:65605944:ACCT:A	donor_gain	1.0000
11:65605944:ACCTC:A	donor_gain	1.0000
11:65605945:C:CC	donor_gain	1.0000
11:65605945:C:G	donor_loss	1.0000
11:65605945:CCT:C	donor_gain	1.0000
11:65605945:CCTC:C	donor_gain	1.0000
11:65605945:CCTCC:C	donor_gain	1.0000
11:65606077:CTCCA:C	acceptor_gain	1.0000
11:65606078:TCCA:T	acceptor_gain	1.0000
11:65606079:CCA:C	acceptor_gain	1.0000
11:65606079:CCAC:C	acceptor_gain	1.0000
11:65606080:CA:C	acceptor_gain	1.0000
11:65606080:CAC:C	acceptor_gain	1.0000
11:65606082:C:CC	acceptor_gain	1.0000
11:65606094:CCGA:C	acceptor_gain	1.0000
11:65606095:C:T	acceptor_gain	1.0000

AlphaMissense

5391 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65606789:A:C	I502S	1.000
11:65606789:A:G	I502T	1.000
11:65606789:A:T	I502N	1.000
11:65606796:G:C	H500D	1.000
11:65606800:G:C	F498L	1.000
11:65606800:G:T	F498L	1.000
11:65606801:A:C	F498C	1.000
11:65606801:A:G	F498S	1.000
11:65606802:A:G	F498L	1.000
11:65607275:G:T	P495Q	1.000
11:65607276:G:A	P495S	1.000
11:65607389:A:G	L457P	1.000
11:65607395:C:G	R455P	1.000
11:65607488:A:G	L424P	1.000
11:65607689:C:A	W399C	1.000
11:65607689:C:G	W399C	1.000
11:65607690:C:G	W399S	1.000
11:65607691:A:G	W399R	1.000
11:65607691:A:T	W399R	1.000
11:65607788:C:A	R366S	1.000
11:65607788:C:G	R366S	1.000
11:65607789:C:A	R366M	1.000
11:65607789:C:G	R366T	1.000
11:65607809:C:A	W359C	1.000
11:65607809:C:G	W359C	1.000
11:65607811:A:G	W359R	1.000
11:65607811:A:T	W359R	1.000
11:65607812:G:C	C358W	1.000
11:65607813:C:T	C358Y	1.000
11:65607930:A:G	L354P	1.000

dbSNP variants (sampled 300 via entrez): RS1000094970 (11:65609960 C>T), RS1000154033 (11:65606515 T>C), RS1000206484 (11:65606665 G>A), RS1000264077 (11:65615806 G>A), RS1000439950 (11:65615942 G>A,T), RS1000716354 (11:65612506 A>C), RS1000802182 (11:65600597 G>A,C), RS1001051301 (11:65614506 G>A,C), RS1001092586 (11:65598720 T>C), RS1001145843 (11:65604783 G>A,C), RS1001446403 (11:65604540 C>T), RS1001586708 (11:65601150 G>A,T), RS1001700256 (11:65599189 G>A), RS1001786993 (11:65610715 G>A), RS1001875717 (11:65615327 T>C)

Disease associations

OMIM: gene MIM:600050 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (1): Moyamoya angiopathy (Orphanet:477768)

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST002481_8	Acne (severe)	3.000000e-11
GCST002773_6	Gout	1.000000e-07
GCST004599_22	Mean platelet volume	7.000000e-20
GCST004606_203	Eosinophil count	1.000000e-18
GCST004624_188	Sum eosinophil basophil counts	3.000000e-18
GCST004773_8	Type 2 diabetes	4.000000e-08
GCST005195_134	Coronary artery disease	2.000000e-11
GCST005196_50	Coronary artery disease	3.000000e-11
GCST005196_51	Coronary artery disease	4.000000e-08
GCST007234_16	Acne (severe)	5.000000e-13
GCST007234_17	Acne (severe)	3.000000e-11
GCST007876_2	Estimated glomerular filtration rate	2.000000e-20
GCST009379_318	Type 2 diabetes	2.000000e-14
GCST010002_240	Refractive error	3.000000e-11
GCST010512_18	Serum uric acid levels	1.000000e-40
GCST90020029_326	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0004761	uric acid measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2708 (SINGLE PROTEIN), CHEMBL6066131 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

42 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 185,459 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2103830	FOSTAMATINIB	4	3,841
CHEMBL2325741	CAPIVASERTIB	4	2,157
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL274654	ORANTINIB	3	3,596
CHEMBL290352	CEP-1347	3	359
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1230609	FORETINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1976040	ADAVOSERTIB	2
CHEMBL3545396	BMS-690514	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL558752	RAF-265	2
CHEMBL564829	MILCICLIB	2
CHEMBL572878	TOZASERTIB	2

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 (4 total), top 4:

Ligand	Action	Affinity	Parameter
compound 8 [PMID: 24044867]	Inhibition	8.52	pIC50
CEP-1347	Inhibition	8.22	pIC50
URMC-099	Inhibition	7.85	pIC50
Sanofi-14h	Inhibition	7.08	pIC50

Binding affinities (BindingDB)

92 measured of 209 human assays (209 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 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
3-(1H-indol-5-yl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 5-(3,4-dimethoxyphenyl)-3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 3-(1H-indol-5-yl)-5-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 3-(1H-indol-5-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 3,5-di(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 5-(3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethylpyridin-2-amine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 3-(1H-indol-5-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 5,5′-(1H-pyrrolo[2,3-b]pyridine-3,5-diyl)bis(N,N-dimethylpyridin-2-amine)	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 5-(3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-amine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 4-(5-(4-amino-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 4-(5-(6-aminopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 5-(3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)pyridin-2-amine	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 1-(1-methyl-1H-indol-5-yl)-6-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
Preparation of 6-(4-hydroxyphenyl)-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
6-(3,4-dimethoxyphenyl)-1- (1H-indol-5-yl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
6-(3-amino-4- methoxyphenyl)-1-(1H- indol-5-yl)-1H-imidazo[4,5- b]pyrazin-2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(1H-indol-5-yl)-6-(4- methoxy-3,5- dimethylphenyl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(1H-indol-5-yl)-6-(4- morpholinophenyl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1,6-di(1H-indol-5-yl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
6-(3-hydroxyphenyl)-1-(1H- indol-5-yl)-1H-imidazo[4,5- b]pyrazin-2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
6-(2,5-difluoro-4- hydroxyphenyl)-1-(1H- indol-5-yl)-1H-imidazo[4,5- b]pyrazin-2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
6-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-1-(1H-indol-5-yl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(1H-indol-5-yl)-6-(3- methoxy-4-(2-(piperazin-1- yl)ethoxy)phenyl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(4-methoxyphenyl)-6- (3,4,5-trimethoxyphenyl)- 1H-imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(2-methyl-1H-indol-5-yl)- 6-(3,4,5-trimethoxyphenyl)- 1H-imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-cyclopentyl-6-(4- hydroxyphenyl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(cyclopropylmethyl)-6- (3,4,5-trimethoxyphenyl)- 1H-imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(cyclopropylmethyl)-6- (3,4-dimethoxyphenyl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
6-(4-hydroxyphenyl)-1-(2- methyl-1H-indol-5-yl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(1H-indazol-6-yl)-6- (3,4,5-trimethoxyphenyl)- 1H-imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
6-(3,4-dimethoxyphenyl)-1- (1H-indazol-6-yl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(1H-indazol-6-yl)-6- (pyridin-4-yl)-1H- imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors
1-(benzo[d]thiazol-5-yl)-6- (3,4,5-trimethoxyphenyl)- 1H-imidazo[4,5-b]pyrazin- 2(3H)-one	IC50	550 nM	US-9814704: Substituted pyrrolo[2,3-b]pyridines as MLK inhibitors

ChEMBL bioactivities

311 potent at pChembl≥5 of 315 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.61	IC50	2.47	nM	STAUROSPORINE
8.52	IC50	3	nM	CHEMBL2436980
8.52	Kd	3	nM	CHEMBL4465866
8.40	Kd	4	nM	CHEMBL4576489
8.40	IC50	4	nM	STAUROSPORINE
8.30	IC50	5.06	nM	STAUROSPORINE
8.30	IC50	5	nM	K-252A
8.22	IC50	6	nM	CEP-1347
8.22	IC50	6	nM	CHEMBL5403058
8.22	IC50	6	nM	CHEMBL5397520
8.15	IC50	7	nM	CHEMBL2436982
8.15	IC50	7	nM	CHEMBL4218417
8.10	IC50	8	nM	CHEMBL5417152
8.05	IC50	9	nM	CHEMBL2436976
7.96	Kd	11	nM	R-406
7.96	IC50	11	nM	CHEMBL289772
7.96	IC50	11	nM	CHEMBL277817
7.96	IC50	11	nM	CHEMBL288817
7.96	IC50	11	nM	CHEMBL5436267
7.92	IC50	12	nM	CHEMBL386636
7.89	IC50	13	nM	CHEMBL416056
7.85	IC50	14	nM	CHEMBL2436978
7.85	IC50	14	nM	CHEMBL5409050
7.85	IC50	14	nM	CHEMBL5416972
7.77	Kd	17	nM	MIDOSTAURIN
7.77	IC50	17	nM	CHEMBL5435826
7.75	Kd	18	nM	LESTAURTINIB
7.72	IC50	19	nM	CHEMBL2436981
7.70	Kd	20	nM	STAUROSPORINE
7.70	IC50	20	nM	CHEMBL299496
7.70	IC50	20	nM	CHEMBL5397819
7.68	IC50	21	nM	CHEMBL2436977
7.68	IC50	21	nM	CHEMBL288229
7.66	IC50	22	nM	CHEMBL374581
7.64	IC50	23	nM	CEP-1347
7.64	IC50	23.1	nM	CEP-1347
7.62	IC50	23.7	nM	CHEMBL5413518
7.60	IC50	25	nM	CHEMBL5421283
7.58	IC50	26	nM	CHEMBL221536
7.58	IC50	26	nM	CHEMBL5436833
7.57	IC50	27	nM	CHEMBL5440213
7.54	Kd	29	nM	R-406
7.51	IC50	31	nM	CHEMBL288816
7.41	IC50	39	nM	STAUROSPORINE
7.40	IC50	40	nM	CHEMBL2436979
7.40	IC50	40	nM	CHEMBL357490
7.36	IC50	44	nM	CHEMBL36891
7.31	IC50	49	nM	STAUROSPORINONE
7.30	Kd	50	nM	PF-03814735
7.28	Kd	52	nM	CHEMBL3688339

PubChem BioAssay actives

191 with measured affinity, of 831 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	2198321: Inhibition of human MLK3 using myelin basic protein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0025	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	1526193: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged MAP3K11 (unknown origin) (99 to 398 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0030	uM
3-(1H-indol-5-yl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine	775326: Inhibition of MLK3 (unknown origin) after 20 mins by scintillation counting analysis in presence of [33P]-ATP	ic50	0.0030	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	1526193: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged MAP3K11 (unknown origin) (99 to 398 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0040	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	1983611: Inhibition of recombinant human N-terminal HA-tagged wild type MLK3	ic50	0.0050	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0060	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0060	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	775352: Inhibition of MLK3 (unknown origin) after 20 mins in presence of [33P]-ATP	ic50	0.0060	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	1384627: Inhibition of recombinant GST-tagged full length human MLK3 KD 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	0.0070	uM
5-[5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-2-amine	775326: Inhibition of MLK3 (unknown origin) after 20 mins by scintillation counting analysis in presence of [33P]-ATP	ic50	0.0070	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0080	uM
5-[5-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-2-amine	775326: Inhibition of MLK3 (unknown origin) after 20 mins by scintillation counting analysis in presence of [33P]-ATP	ic50	0.0090	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	125162: Inhibition of Mixed lineage kinase 3 (MLK3)	ic50	0.0110	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	125162: Inhibition of Mixed lineage kinase 3 (MLK3)	ic50	0.0110	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	125162: Inhibition of Mixed lineage kinase 3 (MLK3)	ic50	0.0110	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	624866: Binding constant for MLK3 kinase domain	kd	0.0110	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0110	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	0.0120	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	277637: Inhibition of GST-MLK3 expressed in baculovirus	ic50	0.0130	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0140	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0140	uM
3-(1H-indol-5-yl)-5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine	775326: Inhibition of MLK3 (unknown origin) after 20 mins by scintillation counting analysis in presence of [33P]-ATP	ic50	0.0140	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0170	uM
Midostaurin	435414: Binding constant for MLK3 kinase domain	kd	0.0170	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	507628: Binding affinity to MLK3	kd	0.0180	uM
5-[3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]pyridin-2-amine	775326: Inhibition of MLK3 (unknown origin) after 20 mins by scintillation counting analysis in presence of [33P]-ATP	ic50	0.0190	uM
methyl (15S,16R)-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	1424473: Inhibition of flag-tagged MLK3 (unknown origin) expressed in human HeLa cells assessed as reduction in enzyme autophosphorylation incubated for 20 mins by immunoprecipitatation	ic50	0.0200	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0200	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	125162: Inhibition of Mixed lineage kinase 3 (MLK3)	ic50	0.0210	uM
5-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrrolo[2,3-b]pyridine	775326: Inhibition of MLK3 (unknown origin) after 20 mins by scintillation counting analysis in presence of [33P]-ATP	ic50	0.0210	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	0.0220	uM
2-[4-[[4-[3-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazin-1-yl]ethanol	1983616: Inhibition of MLK3 (unknown origin)	ic50	0.0237	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0250	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0260	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	0.0260	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0270	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	125162: Inhibition of Mixed lineage kinase 3 (MLK3)	ic50	0.0310	uM
3-(1H-indol-5-yl)-5-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2-one	775326: Inhibition of MLK3 (unknown origin) after 20 mins by scintillation counting analysis in presence of [33P]-ATP	ic50	0.0400	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	0.0400	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	125162: Inhibition of Mixed lineage kinase 3 (MLK3)	ic50	0.0440	uM
3,13,23-triazahexacyclo[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	0.0490	uM
N-[2-[4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide	1425045: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0500	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425045: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0520	uM
2-[(3S)-3-aminopiperidin-1-yl]-4-[3-(trifluoromethyl)anilino]pyrimidine-5-carboxamide	1668845: Inhibition of human MLK3 using myelin basic protein as substrate in presence of [gamma-33P]-ATP by hotspot kinase assay	ic50	0.0520	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	0.0550	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	125162: Inhibition of Mixed lineage kinase 3 (MLK3)	ic50	0.0560	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425045: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0560	uM
3-[[6-bromo-2-[2,5-dimethyl-1-[3-(morpholine-4-carbonyl)phenyl]pyrrol-3-yl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]benzenesulfonamide	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0570	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	0.0580	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	1984556: Inhibition of human MLK3 by ATP-competitive binding assay	ic50	0.0630	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
Air Pollutants	increases abundance, increases oxidation, affects expression, affects cotreatment, decreases expression	2
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
muconaldehyde	decreases expression	1
methacrylaldehyde	decreases expression, increases oxidation, increases abundance, affects cotreatment	1
perfluoro-n-nonanoic acid	decreases expression	1
GW 7604	increases expression	1
NSC 23766	decreases reaction, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Fulvestrant	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
Caffeine	decreases phosphorylation	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	increases phosphorylation	1
Poly I-C	increases phosphorylation	1
Selenomethionine	affects expression	1
Smoke	decreases expression	1
Sulfates	affects methylation	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	increases expression	1

ChEMBL screening assays

299 unique, capped per target: 299 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003946	Binding	Inhibition of GST-fused human MLK3	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

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1GC	Abcam A-549 MAP3K11 KO 1	Cancer cell line	Male
CVCL_B1WH	Abcam HeLa MAP3K11 KO	Cancer cell line	Female
CVCL_B2NW	Abcam A-549 MAP3K11 KO 2	Cancer cell line	Male
CVCL_B8K2	Abcam HCT 116 MAP3K11 KO	Cancer cell line	Male
CVCL_B8YJ	Abcam MCF-7 MAP3K11 KO	Cancer cell line	Female
CVCL_B9CQ	Abcam A-549 MAP3K11 KO 3	Cancer cell line	Male
CVCL_D8PY	Ubigene HCT 116 MAP3K11 KO	Cancer cell line	Male
CVCL_D9J9	Ubigene HEK293 MAP3K11 KO	Transformed cell line	Female
CVCL_SW58	HAP1 MAP3K11 (-) 1	Cancer cell line	Male
CVCL_SW59	HAP1 MAP3K11 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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