MAP4K4

Summary

MAP4K4 (mitogen-activated protein kinase kinase kinase kinase 4, HGNC:6866) is a protein-coding gene on chromosome 2q11.2, encoding Mitogen-activated protein kinase kinase kinase kinase 4 (O95819). Serine/threonine kinase that plays a role in the response to environmental stress and cytokines such as TNF.

The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 9448 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RASopathy (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 280 total — 5 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 62 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001395002

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6866
Approved symbol	MAP4K4
Name	mitogen-activated protein kinase kinase kinase kinase 4
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	HGK, NIK, FLH21957
Ensembl gene	ENSG00000071054
Ensembl biotype	protein_coding
OMIM	604666
Entrez	9448

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 46 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000324219, ENST00000347699, ENST00000350878, ENST00000413150, ENST00000417294, ENST00000418101, ENST00000421882, ENST00000425019, ENST00000427603, ENST00000456652, ENST00000476609, ENST00000477711, ENST00000489490, ENST00000491743, ENST00000498066, ENST00000625522, ENST00000627726, ENST00000634702, ENST00000902130, ENST00000902131, ENST00000902132, ENST00000902133, ENST00000902134, ENST00000902135, ENST00000902136, ENST00000902137, ENST00000902138, ENST00000902139, ENST00000902140, ENST00000902141, ENST00000933918, ENST00000933919, ENST00000933920, ENST00000933921, ENST00000933922, ENST00000933923, ENST00000933924, ENST00000933925, ENST00000971082, ENST00000971083, ENST00000971084, ENST00000971085, ENST00000971086, ENST00000971087, ENST00000971088, ENST00000971089, ENST00000971090, ENST00000971091, ENST00000971092, ENST00000971093, ENST00000971094, ENST00000971095

RefSeq mRNA: 51 — MANE Select: NM_001395002 NM_001242559, NM_001242560, NM_001384476, NM_001384477, NM_001384478, NM_001384481, NM_001384482, NM_001384483, NM_001384484, NM_001384485, NM_001384486, NM_001384487, NM_001384488, NM_001384490, NM_001384491, NM_001384492, NM_001384493, NM_001384494, NM_001384495, NM_001384496, NM_001384497, NM_001384506, NM_001384507, NM_001384508, NM_001384509, NM_001384520, NM_001384543, NM_001384548, NM_001384549, NM_001384550, NM_001384551, NM_001384552, NM_001384553, NM_001384554, NM_001384555, NM_001384556, NM_001384557, NM_001384558, NM_001384559, NM_001384560, NM_001384561, NM_001384562, NM_001384563, NM_001384564, NM_001384567, NM_001384572, NM_001384579, NM_001395002, NM_004834, NM_145686, NM_145687

CCDS: CCDS56130, CCDS74546, CCDS82487, CCDS92821, CCDS92822, CCDS92823

Canonical transcript exons

ENST00000324219 — 33 exons

Exon	Start	End
ENSE00000487322	101863821	101864051
ENSE00000487323	101864930	101865036
ENSE00000772385	101887088	101887237
ENSE00000804313	101859643	101859864
ENSE00000804316	101860825	101860986
ENSE00000804320	101866428	101866579
ENSE00000804327	101870295	101870415
ENSE00000804328	101873647	101873764
ENSE00000804330	101874082	101874252
ENSE00000804337	101885187	101885287
ENSE00001164070	101891166	101894690
ENSE00001245992	101867212	101867309
ENSE00001664914	101871494	101871685
ENSE00002454229	101882551	101882685
ENSE00002480780	101877003	101877146
ENSE00002481953	101888796	101888935
ENSE00002483412	101887778	101887937
ENSE00003479306	101842609	101842681
ENSE00003489699	101834409	101834463
ENSE00003537648	101829504	101829594
ENSE00003576110	101831721	101831851
ENSE00003582366	101855977	101856138
ENSE00003644120	101825319	101825429
ENSE00003656406	101839819	101839994
ENSE00003659351	101858996	101859082
ENSE00003676626	101869622	101869797
ENSE00003687874	101844101	101844311
ENSE00003692101	101835900	101835978
ENSE00003720539	101790720	101790776
ENSE00003733723	101698473	101698538
ENSE00003744489	101697707	101698137
ENSE00003748700	101868029	101868037
ENSE00003788894	101823928	101824053

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 78.6716 / max 1519.6763, expressed in 1817 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21625	72.8044	1817
21642	2.3874	920
21638	2.3698	983
21637	0.5206	216
21626	0.2024	67
21632	0.1820	58
21644	0.1657	67
21633	0.0393	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.00	gold quality
cortical plate	UBERON:0005343	98.89	gold quality
ganglionic eminence	UBERON:0004023	98.81	gold quality
corpus callosum	UBERON:0002336	98.49	gold quality
medial globus pallidus	UBERON:0002477	98.42	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.42	gold quality
spinal cord	UBERON:0002240	98.41	gold quality
globus pallidus	UBERON:0001875	98.34	gold quality
sural nerve	UBERON:0015488	98.34	gold quality
inferior olivary complex	UBERON:0002127	98.21	gold quality
ventricular zone	UBERON:0003053	97.89	gold quality
lateral globus pallidus	UBERON:0002476	97.85	gold quality
amygdala	UBERON:0001876	97.70	gold quality
substantia nigra	UBERON:0002038	97.66	gold quality
cranial nerve II	UBERON:0000941	97.61	gold quality
midbrain	UBERON:0001891	97.50	gold quality
subthalamic nucleus	UBERON:0001906	97.47	gold quality
inferior vagus X ganglion	UBERON:0005363	97.47	gold quality
putamen	UBERON:0001874	97.38	gold quality
stromal cell of endometrium	CL:0002255	97.35	gold quality
Ammon’s horn	UBERON:0001954	97.27	gold quality
hypothalamus	UBERON:0001898	96.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.77	gold quality
medulla oblongata	UBERON:0001896	96.72	gold quality
caudate nucleus	UBERON:0001873	96.37	gold quality
islet of Langerhans	UBERON:0000006	96.13	gold quality
temporal lobe	UBERON:0001871	96.05	gold quality
nucleus accumbens	UBERON:0001882	95.87	gold quality
ventral tegmental area	UBERON:0002691	95.74	gold quality
embryo	UBERON:0000922	95.73	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	83.11
E-MTAB-8142	yes	72.96
E-HCAD-25	yes	56.42
E-CURD-10	no	982.28
E-MTAB-8271	no	409.85
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, FOXC1, NKX3-1, PPARG, TP53

miRNA regulators (miRDB)

178 targeting MAP4K4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-12136	99.98	72.81	5713

Literature-anchored findings (GeneRIF, showing 40)

• interaction with GBP3 (PMID:12387898)
• The STE20 kinase HGK is broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion. (PMID:12612079)
• MAP4K4 is a putative effector of Rap2, a Ras family small GTP-binding protein, mediating the activation of JNK by Rap2 (PMID:14966141)
• studies of the promigratory role of MAP4K4 showed that the knockdown of this transcript inhibited the migration of multiple carcinoma cell lines, indicating a broad role in cell motility (PMID:16537454)
• MAP4K4 silencing prevents TNFa-induced insulin resistance in human skeletal muscle and restores appropriate signaling inputs to enhance glucose uptake (PMID:17227768)
• MAP4K4 expression significantly correlated with overall and recurrence-free survival (P=0.025 and 0.004) independent of age, tumor size, differentiation, and stage. (PMID:18981001)
• Results identify MAP4K4 as a key upstream mediator of TNF-alpha action on the beta cell, preventing tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion. (PMID:19690174)
• Data show that down-regulation of hepatocyte progenitor kinase-like kinase (HGK) can obviously inhibit the migration and invasion of HepG2 cells in vitro, and suggest that HGK may be a new therapeutic target for treatment of hepatocellular carcinoma. (PMID:20857524)
• MAP4K4 overexpression is an independent predictor of poor prognosis of Hepatocellular Carcinoma patients, and inhibition of its expression might be of therapeutic significance (PMID:21196414)
• Elevated MAP4K4 expression is closely associated with lung adenocarcinoma progression with independent prognostic value in predicting overall survival for patients with lung adenocarcinoma. (PMID:22824148)
• Common polymorphisms in MAP4K4 are associated with insulin resistance and beta-cell dysfunction, possibly via this gene’s role in inflammatory signaling. (PMID:23094072)
• TRAF1.NIK is a central complex linking canonical and non-canonical pathways by disrupting the TRAF2-cIAP2 ubiquitin ligase complex (PMID:23543740)
• results reveal a key target of SOX2 expression and highlight the unexpected context-dependent role for MAP4K4, a pluripotent activator of several mitogen-activated protein kinase pathways, in regulating tumor cell survival. (PMID:24233838)
• that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation (PMID:24244164)
• loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target (PMID:25799996)
• The results of the present study suggested that inhibition of MAP4K4 may be a therapeutic strategy for gastric cancer. (PMID:26549737)
• miR-194 regulated the progression of hepatocellular carcinoma through directly inhibiting the expression of MAP4K4 (PMID:26722431)
• This report identifies HGK methylation/downregulation in T cells as a potential biomarker for non-obese type 2 diabetes (PMID:26918832)
• MAP4K4 promotes the epithelial-mesenchymal transition and invasiveness of hepatocellular carcinoma cells (PMID:27010469)
• Results reveal that endothelial Map4k4 is critical for lymphatic vascular development by regulating endothelial cells (EC)quiescence and lymphatic EC fate. (PMID:27044870)
• of the five variants, SNP rs2236935T/C was significantly associated with type 2 diabetes mellitus (T2DM) in this study population; conclude that MAP4K4 gene is associated with T2DM in a Chinese Han population, and MAP4K4 gene variants may contribute to the risk toward the development of T2DM (PMID:27174326)
• Interactions between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to non-obese T2D. (PMID:28061846)
• these findings identify MAP4K4 as a novel MAPK/ERK pathway regulator in lung adenocarcinoma that is required for lung adenocarcinoma maintenance. (PMID:28306189)
• the close proximity between AcSDKP and FGFR1 was essential for the suppression of TGFbeta/smad signaling and EndMT associated with MAP4K4 phosphorylation (P-MAP4K4) in endothelial cells. (PMID:28771231)
• Results show that MAP4K4 is a target gene for the novel miR-TG. Its expression is up-regulated in papillary thyroid carcinoma (PTC) which is inversely correlated with that of miR-TG. (PMID:28855631)
• RBM4-SRSF3-MAP4K4 constitutes a novel mechanism for manipulating the metastasis of colorectal cancer cells through the JNK1 signaling pathway. (PMID:29138007)
• miR-200c could suppress cervical cancer cell proliferation and progression via regulating MAP4K4, which might provide a new target for cervical cancer diagnosis and therapy (PMID:29461619)
• an anti-cancer effect of microRNA-141 on breast cancer by cytotoxic CD4+ T cells through MAP4K4 expression. (PMID:29620289)
• These results suggest that downregulation of miR-98-5p promotes tumor development by downregulation of MAP4K4 and inhibition of the downstream MAPK/ERK signaling (PMID:29970191)
• TIIA triggered HGK/JNK1-dependent Jun activation and led to increased Jun recruitment to AP-1-binding site in the SESN2 promoter region. (PMID:30258193)
• Our findings showed that 5-FU inhibited malignant behavior of human colorectal cancer (CRC) cells in vitro and in vivo by enhancing the efficiency of miR-141 Our data suggested that targetting the miR-141/MAP4K4 signaling pathway could be a potential molecular target that may enhance chemotherapeutic efficacy in the treatment of CRC (PMID:30429233)
• These studies highlight a MAP4K4-initiated signaling cascade that induces motor neuron degeneration. (PMID:30699345)
• Targeted genomic CRISPR-Cas9 screen identifies MAP4K4 as essential for glioblastoma invasion. (PMID:31570734)
• STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells. (PMID:31913126)
• MAP4K4 negatively regulates CD8 T cell-mediated antitumor and antiviral immunity. (PMID:32220977)
• HGK promotes metastatic dissemination in prostate cancer. (PMID:34112843)
• MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3. (PMID:34511598)
• MAP4K4 mediates the SOX6-induced autophagy and reduces the chemosensitivity of cervical cancer. (PMID:34930918)
• MiR-181c suppresses triple-negative breast cancer tumorigenesis by targeting MAP4K4. (PMID:35026645)
• Bioinformatics and Experimental Analyses Reveal MAP4K4 as a Potential Marker for Gastric Cancer. (PMID:36292671)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	map4k4	ENSDARG00000098670
mus_musculus	Map4k4	ENSMUSG00000026074
rattus_norvegicus	Map4k4	ENSRNOG00000014013

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), NEK4 (ENSG00000114904), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), PAK1 (ENSG00000149269), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase kinase 4 — O95819 (reviewed: O95819)

Alternative names: HPK/GCK-like kinase HGK, MAPK/ERK kinase kinase kinase 4, Nck-interacting kinase

All UniProt accessions (11): O95819, A0A0D9SEY1, E7EN19, E7ENQ1, E7ETN6, E7EX83, G5E948, H7C0P6, H7C360, H7C3Z6, V9HWH3

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase that plays a role in the response to environmental stress and cytokines such as TNF. Appears to act upstream of the JUN N-terminal pathway. Activator of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. MAP4Ks act in parallel to and are partially redundant with STK3/MST2 and STK4/MST2 in the phosphorylation and activation of LATS1/2, and establish MAP4Ks as components of the expanded Hippo pathway. Phosphorylates SMAD1 on Thr-322.

Subunit / interactions. Interacts with the SH3 domain of the adapter proteins Nck. Interacts (via its CNH regulatory domain) with ATL1 (via the N-terminal region). Interacts with RAP2A (GTP-bound form preferentially).

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed. Isoform 5 is abundant in the brain. Isoform 4 is predominant in the liver, skeletal muscle and placenta.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
O95819-1	1, Tumor-associated	yes
O95819-2	2
O95819-3	3
O95819-4	4, HGK-S
O95819-5	5, HGK-L
O95819-6	6

RefSeq proteins (51): NP_001229488, NP_001229489, NP_001371405, NP_001371406, NP_001371407, NP_001371410, NP_001371411, NP_001371412, NP_001371413, NP_001371414, NP_001371415, NP_001371416, NP_001371417, NP_001371419, NP_001371420, NP_001371421, NP_001371422, NP_001371423, NP_001371424, NP_001371425, NP_001371426, NP_001371435, NP_001371436, NP_001371437, NP_001371438, NP_001371449, NP_001371472, NP_001371477, NP_001371478, NP_001371479, NP_001371480, NP_001371481, NP_001371482, NP_001371483, NP_001371484, NP_001371485, NP_001371486, NP_001371487, NP_001371488, NP_001371489, NP_001371490, NP_001371491, NP_001371492, NP_001371493, NP_001371496, NP_001371501, NP_001371508, NP_001381931, NP_004825, NP_663719, NP_663720 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001180	CNH_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR051700	STE20_Ser-Thr_kinase	Family

Pfam: PF00069, PF00780

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 (92 total): modified residue 28, helix 16, compositionally biased region 12, strand 10, splice variant 7, turn 5, region of interest 4, domain 2, binding site 2, sequence variant 2, initiator methionine 1, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4U3Y	X-RAY DIFFRACTION	1.45
4U3Z	X-RAY DIFFRACTION	2.09
4OBO	X-RAY DIFFRACTION	2.1
4U43	X-RAY DIFFRACTION	2.18
8V5I	X-RAY DIFFRACTION	2.18
4OBQ	X-RAY DIFFRACTION	2.19
4U41	X-RAY DIFFRACTION	2.2
4OBP	X-RAY DIFFRACTION	2.27
4ZP5	X-RAY DIFFRACTION	2.29
4U40	X-RAY DIFFRACTION	2.3
5W5Q	X-RAY DIFFRACTION	2.33
4RVT	X-RAY DIFFRACTION	2.4
4U44	X-RAY DIFFRACTION	2.43
5J95	X-RAY DIFFRACTION	2.5
4U42	X-RAY DIFFRACTION	2.5
4U45	X-RAY DIFFRACTION	2.58
4ZK5	X-RAY DIFFRACTION	2.89
5DI1	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95819-F1	66.47	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): 153 (proton acceptor)

Ligand- & substrate-binding residues (2): 31–39; 54

Post-translational modifications (28): 2, 5, 324, 326, 629, 631, 639, 644, 656, 700, 712, 715, 791, 800, 801, 805, 823, 828, 852, 855 …

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 451 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GCM_MAP4K4, GCM_PTPRD, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_FOCAL_ADHESION_ASSEMBLY, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_HIPPO_SIGNALING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, PATIL_LIVER_CANCER

GO Biological Process (19): MAPK cascade (GO:0000165), negative regulation of cell-matrix adhesion (GO:0001953), protein phosphorylation (GO:0006468), positive regulation of cell migration (GO:0030335), positive regulation of ARF protein signal transduction (GO:0032014), positive regulation of hippo signaling (GO:0035332), intracellular signal transduction (GO:0035556), negative regulation of apoptotic process (GO:0043066), regulation of MAPK cascade (GO:0043408), regulation of JNK cascade (GO:0046328), neuron projection morphogenesis (GO:0048812), positive regulation of keratinocyte migration (GO:0051549), positive regulation of focal adhesion assembly (GO:0051894), positive regulation of focal adhesion disassembly (GO:0120183), negative regulation of neuron projection development (GO:0010977), hippo signaling (GO:0035329), negative regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061179), negative regulation of neuron projection regeneration (GO:0070571), positive regulation of intracellular signal transduction (GO:1902533)

GO Molecular Function (11): creatine kinase activity (GO:0004111), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), microtubule binding (GO:0008017), MAP kinase kinase kinase kinase activity (GO:0008349), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): cytoplasm (GO:0005737), focal adhesion (GO:0005925)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular Senescence	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
MAPK cascade	2
regulation of intracellular signal transduction	2
neuron projection development	2
positive regulation of cell-substrate junction organization	2
intracellular signal transduction	2
negative regulation of response to stimulus	2
kinase activity	2
protein kinase activity	2
intracellular signaling cassette	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
phosphorylation	1
protein modification process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
ARF protein signal transduction	1
regulation of ARF protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
hippo signaling	1
regulation of hippo signaling	1
positive regulation of intracellular signal transduction	1
signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
JNK cascade	1
regulation of MAPK cascade	1
plasma membrane bounded cell projection morphogenesis	1
positive regulation of epithelial cell migration	1
keratinocyte migration	1
regulation of keratinocyte migration	1
positive regulation of cell-matrix adhesion	1
focal adhesion assembly	1
regulation of focal adhesion assembly	1
positive regulation of cell junction assembly	1
focal adhesion disassembly	1
regulation of focal adhesion disassembly	1

Protein interactions and networks

STRING

1520 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP4K4	STRN	O43815	706
MAP4K4	MAPRE2	Q15555	700
MAP4K4	STRN4	Q9NRL3	634
MAP4K4	NCK1	P16333	611
MAP4K4	MSN	P26038	591
MAP4K4	RDX	P35241	574
MAP4K4	GCKR	Q14397	549
MAP4K4	MAP3K1	Q13233	516
MAP4K4	EXOC2	Q96KP1	514
MAP4K4	MAP4K5	Q9Y4K4	513
MAP4K4	LATS2	Q9NRM7	510
MAP4K4	GBP3	Q9H0R5	504
MAP4K4	PDCD10	Q9BUL8	493
MAP4K4	ATL1	Q8WXF7	487
MAP4K4	KIF26B	Q2KJY2	483

IntAct

141 interactions, top by confidence:

A	B	Type	Score
STK25	STRN	psi-mi:“MI:0914”(association)	0.900
STRN3	STRN	psi-mi:“MI:0914”(association)	0.880
STK24	STRN	psi-mi:“MI:0914”(association)	0.870
CNOT6L	CNOT1	psi-mi:“MI:0914”(association)	0.810
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MINK1	MAP4K4	psi-mi:“MI:0915”(physical association)	0.670
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
GBP3	MAP4K4	psi-mi:“MI:0915”(physical association)	0.590
GBP3	MAP4K4	psi-mi:“MI:0407”(direct interaction)	0.590
MAP4K4	GBP3	psi-mi:“MI:0915”(physical association)	0.590
MINK1	CNOT1	psi-mi:“MI:0914”(association)	0.530
MAP4K4	STRN	psi-mi:“MI:0914”(association)	0.530
FANCD2OS	CNOT1	psi-mi:“MI:0914”(association)	0.530
LTBR	ZNF724	psi-mi:“MI:0914”(association)	0.530
SLC9A8	ZNF432	psi-mi:“MI:0914”(association)	0.530
RAP2C	MAP4K4	psi-mi:“MI:0914”(association)	0.530
STRN	MAP4K4	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
ZNRD2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
DISC1	MAP4K4	psi-mi:“MI:0915”(physical association)	0.500
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
MOB1B	PPP6C	psi-mi:“MI:2364”(proximity)	0.480
SFN	MAP4K4	psi-mi:“MI:0915”(physical association)	0.470

BioGRID (314): MAP4K4 (Two-hybrid), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), MAP4K4 (Affinity Capture-MS), CDK12 (Co-fractionation), NOP2 (Co-fractionation), MAP4K4 (Proximity Label-MS), MAP4K4 (Proximity Label-MS), MAP4K4 (Proximity Label-MS)

ESM2 similar proteins: A0A8C0NGY6, A1ZAU8, A2BEA6, A7EQA8, A7Z019, B3DM47, D6C652, F1LP90, H2LBU8, O00470, O01737, O95819, O95835, P25439, P34333, P34428, P34545, P40427, P46937, P51531, P51532, P79937, P83510, P97820, Q03468, Q0CA78, Q1DUF9, Q1L8J7, Q29CT2, Q3TKT4, Q5BAZ5, Q5XGD9, Q60954, Q61X54, Q62431, Q6AW06, Q6C3D7, Q6DIC0, Q6DRG1, Q6GQD7

Diamond homologs: A0A194VNL2, A0A1S4CGX4, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, A9RWC9, A9S5R3, A9SR33, B0XPE4, C4YLK8, E1BK52, F1NBT0, G4N6Z6, G4NEB8, G5EDF7, O00506, O09110, O14733, O54748, O80396, O94804, O95819, P06784, P08018, P0CY25, P10506, P29678, P31938, P32490, P32491, P33886, P36506, P36507, P45985, P46734

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
MAP4K4	“down-regulates activity”	SMAD1	phosphorylation
MAP4K4	“up-regulates activity”	MAP3K11	phosphorylation
MAP4K4	“down-regulates quantity”	TRAF2	phosphorylation
MAP4K4	“up-regulates activity”		phosphorylation
MAP4K4	up-regulates	MAP3K1	phosphorylation
MAP4K4	up-regulates	MAP3K7	binding
MAP4K4	“down-regulates activity”	PIK3CA	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	32.9×	1e-04
SHC1 events in ERBB2 signaling	5	23.3×	2e-04
Signaling by FGFR1 in disease	6	17.2×	1e-04
NCAM signaling for neurite out-growth	5	13.3×	8e-04
Signaling by SCF-KIT	5	12.2×	1e-03
Apoptosis	7	11.5×	2e-04
EPH-ephrin mediated repulsion of cells	5	10.8×	2e-03
SARS-CoV-1-host interactions	6	10.3×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
MAPK cascade	9	10.2×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	8
Uncertain significance	166
Likely benign	10
Benign	45

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
3543005	NM_001395002.1(MAP4K4):c.629A>G (p.Tyr210Cys)	Pathogenic
3543006	NM_001395002.1(MAP4K4):c.375del (p.Glu127fs)	Pathogenic
3543008	NM_001395002.1(MAP4K4):c.518G>A (p.Gly173Asp)	Pathogenic
3870333	NM_001395002.1(MAP4K4):c.3985C>T (p.Arg1329Ter)	Pathogenic
4103562	NM_001395002.1(MAP4K4):c.1204C>T (p.Gln402Ter)	Pathogenic
1804004	NM_001395002.1(MAP4K4):c.3458_3459del (p.Val1153fs)	Likely pathogenic
2578366	NM_001395002.1(MAP4K4):c.583A>G (p.Met195Val)	Likely pathogenic
3340992	NM_001395002.1(MAP4K4):c.52del (p.Leu18fs)	Likely pathogenic
3374718	NM_001395002.1(MAP4K4):c.514T>A (p.Phe172Ile)	Likely pathogenic
4103555	NM_001395002.1(MAP4K4):c.608A>G (p.Asp203Gly)	Likely pathogenic
4624277	NM_001395002.1(MAP4K4):c.161A>G (p.Lys54Arg)	Likely pathogenic
4796489	NM_001395002.1(MAP4K4):c.298C>T (p.Gln100Ter)	Likely pathogenic
545107	NM_001395002.1(MAP4K4):c.1694G>A (p.Arg565Gln)	Likely pathogenic

SpliceAI

5380 predictions. Top by Δscore:

Variant	Effect	Δscore
2:101698134:GCGG:G	donor_gain	1.0000
2:101698136:GG:G	donor_gain	1.0000
2:101698137:GG:G	donor_gain	1.0000
2:101790710:T:A	acceptor_gain	1.0000
2:101790714:TTTCA:T	acceptor_loss	1.0000
2:101790715:TTCAG:T	acceptor_loss	1.0000
2:101790717:CA:C	acceptor_loss	1.0000
2:101790718:A:AG	acceptor_gain	1.0000
2:101790718:A:G	acceptor_loss	1.0000
2:101790718:AG:A	acceptor_gain	1.0000
2:101790719:G:A	acceptor_gain	1.0000
2:101790719:G:GG	acceptor_gain	1.0000
2:101790719:G:T	acceptor_loss	1.0000
2:101790719:GGGT:G	acceptor_gain	1.0000
2:101790719:GGGTC:G	acceptor_gain	1.0000
2:101790777:G:GC	donor_loss	1.0000
2:101790778:T:A	donor_loss	1.0000
2:101823923:A:AG	acceptor_gain	1.0000
2:101823923:ATAAG:A	acceptor_gain	1.0000
2:101823924:T:G	acceptor_gain	1.0000
2:101823924:TAAGG:T	acceptor_loss	1.0000
2:101823925:A:AG	acceptor_gain	1.0000
2:101823925:AAG:A	acceptor_gain	1.0000
2:101823926:A:G	acceptor_gain	1.0000
2:101823926:AGG:A	acceptor_loss	1.0000
2:101823927:G:GA	acceptor_loss	1.0000
2:101825316:T:G	acceptor_gain	1.0000
2:101825316:TA:T	acceptor_loss	1.0000
2:101825317:A:AG	acceptor_gain	1.0000
2:101825317:A:AT	acceptor_loss	1.0000

AlphaMissense

9095 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:101698133:T:C	L18P	1.000
2:101698488:T:C	F25L	1.000
2:101698489:T:C	F25S	1.000
2:101698489:T:G	F25C	1.000
2:101698490:T:A	F25L	1.000
2:101698490:T:G	F25L	1.000
2:101790720:G:C	G42R	1.000
2:101790721:G:A	G42D	1.000
2:101790751:C:A	A52D	1.000
2:101790754:T:A	I53N	1.000
2:101790760:T:A	V55D	1.000
2:101790769:T:A	V58D	1.000
2:101823944:T:G	I66S	1.000
2:101823965:T:C	L73P	1.000
2:101824006:G:C	G87R	1.000
2:101824007:G:A	G87D	1.000
2:101824010:C:A	A88D	1.000
2:101824012:T:C	F89L	1.000
2:101824013:T:C	F89S	1.000
2:101824013:T:G	F89C	1.000
2:101824014:C:A	F89L	1.000
2:101824014:C:G	F89L	1.000
2:101824049:T:C	L101P	1.000
2:101824051:T:A	W102R	1.000
2:101824051:T:C	W102R	1.000
2:101825320:T:C	L103P	1.000
2:101825323:T:A	V104D	1.000
2:101825331:T:C	F107L	1.000
2:101825332:T:C	F107S	1.000
2:101825333:C:A	F107L	1.000

dbSNP variants (sampled 300 via entrez): RS1000012310 (2:101860258 C>T), RS1000013037 (2:101731193 T>C), RS1000028492 (2:101725144 T>G), RS1000034096 (2:101716258 A>G), RS1000063305 (2:101860714 A>C), RS1000075152 (2:101830195 T>A), RS1000080340 (2:101725511 T>C), RS1000099233 (2:101867322 C>T), RS1000171205 (2:101854693 A>G), RS1000173585 (2:101810880 T>C,G), RS1000182675 (2:101769486 A>G), RS1000185224 (2:101812019 T>C), RS1000216329 (2:101811661 C>T), RS1000221933 (2:101854884 T>G), RS1000240677 (2:101762894 T>C)

Disease associations

OMIM: gene MIM:604666 | disease phenotypes: MIM:207500, MIM:301800, MIM:601371, MIM:108010

GenCC curated gene-disease

Disease	Classification	Inheritance
RASopathy	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (6): imperforate anus (MONDO:0001046), renal dysplasia (MONDO:0019638), RASopathy (MONDO:0021060), early-onset non-syndromic cataract (MONDO:0011060), arteriovenous malformations of the brain (MONDO:0007154), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (5): Non-syndromic anorectal malformation (Orphanet:557), Renal dysplasia (Orphanet:93108), RASopathy (Orphanet:536391), Early onset non-syndromic cataract (Orphanet:91492), Brain arteriovenous malformation (Orphanet:46724)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000110	Renal dysplasia

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001877_12	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	3.000000e-06
GCST007600_63	Alzheimer’s disease	5.000000e-06
GCST008838_6	Asthma (time to onset)	2.000000e-07
GCST008916_13	Asthma	8.000000e-13
GCST008916_29	Asthma	2.000000e-60
GCST009325_36	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	8.000000e-13
GCST90002407_56	White blood cell count	5.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001006	Anus, Imperforate	C06.198.050; C16.131.314.094
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6166 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

62 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 443,447 (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
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL180022	NERATINIB	4	9,404
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL576982	QUIZARTINIB	4	4,432
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL939	GEFITINIB	4	117,814
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL217092	SARACATINIB	3	3,982
CHEMBL270995	BRIVANIB ALANINATE	3
CHEMBL3544983	TESEVATINIB	3
CHEMBL377300	BRIVANIB	3
CHEMBL38380	FASUDIL	3
CHEMBL491473	CEDIRANIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL572881	MOTESANIB	3
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230609	FORETINIB	2

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4550690	Toxicity	3	anastrozole;exemestane	Breast Neoplasms

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4550690	MAP4K4	3	0.00	1	anastrozole;exemestane

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — MSN subfamily

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
famlasertib	Inhibition	9.52	pIC50
PF06260933	Inhibition	8.43	pIC50
compound 26 [PMID: 24673130]	Inhibition	7.77	pIC50
compound 21 [PMID: 23312943]	Inhibition	7.74	pIC50

Binding affinities (BindingDB)

424 measured of 425 human assays (425 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-	KI	0.06 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1-Cyclopropyl-3-(7-fluoro-6-(8-methyl- 2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)urea	KI	0.2 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
7-Azaspiro[3.5]nonan-2-yl (7-fluoro-6- (8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	0.27 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
2-Azaspiro[3.3]heptan-6-yl (7-fluoro-6- (8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	0.34 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
2-(3-Azabicyclo[3.1.0]hexan-6-yl)ethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	0.44 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
6-Azaspiro[3.4]octan-2-yl (7-fluoro-6- (8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	0.47 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1-(Cyclopropylmethyl)-3-(7-fluoro-6- (8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)urea	KI	0.5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(1R,5S,6s)-3-Azabicyclo[3.1.0]hexan-6-	KI	0.58 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1-(Azetidin-3-yl)-3-(7-fluoro-6-(8- methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)urea	KI	0.76 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
6-(8-methyl-2,3-dihydro-1H-	KI	0.78 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(1R,2S)-2-Cyanocyclopentyl (8-chloro-	KI	0.805 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1-(7-Fluoro-6-(8-methyl-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)-3-(tetrahydro-2H- pyran-4-yl)urea	KI	0.83 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(R)-1-(7-Fluoro-6-(8-methyl-2,3-	KI	0.88 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(1R,2S,3R)-2-Ethyl-N-(7-fluoro-6-(8-	KI	0.9 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1-(Methylcarbamoyl)azetidin-3-yl (7- fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	0.91 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
7-fluoro-6-(8-methyl-2,3-dihydro-1H-	KI	0.945 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(R)-1-(7-Fluoro-6-(8-methyl-2,3-	KI	0.95 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
7-Methyl-7-azaspiro[3.5]nonan-2-yl (7- fluoro-6-(4-methyl-5,6,7,8-tetrahydro- 1,5-naphthyridin-3-yl)isoquinolin-3- yl)carbamate	KI	1.07 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
fluoro-6-(8-methyl-2,3-dihydro-1H-	KI	1.1 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
2-Methyl-2-azaspiro[3.3]heptan-6-yl (7-fluoro-6-(4-methyl-5,6,7,8- tetrahydro-1,5-naphthyridin-3- yl)isoquinolin-3-yl)carbamate	KI	1.15 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
3-Methoxybutyl (7-fluoro-6-(8-methyl- 2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	1.5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
Staurosporine	KD	1.7 nM
(1-methyl-1H-pyrazol-4-	KI	1.8 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
Pyrrolidin-3-ylmethyl (7-fluoro-6-(8- methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	2.1 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
MAP02	KI	2.2 nM
(3-Fluoropyrrolidin-3-yl)methyl (7- fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	2.4 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(1R,2S)-2-Cyanocyclopentyl (7-fluoro-	KI	2.5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-	KI	2.5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
Cyclopropylmethyl (7-fluoro-6-(8- methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	2.7 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1-Acetylazetidin-3-yl (7-fluoro-6-(8- methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	2.9 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
MAP19	IC50	3.11 nM	US-9855269: Aminoquinazoline and pyridopyrimidine derivatives
7-fluoro-6-(8-methyl-2,3-dihydro-1H-	KI	3.75 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
MAP01	IC50	3.79 nM
MAP12	IC50	3.88 nM
1-Oxa-7-azaspiro[4.4]nonan-3-yl (7- fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	4 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(4-Fluoropiperidin-4-yl)methyl (7- fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	4 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
(R)-1-(1-Cyanopropan-2-yl)-3-(7-	KI	4 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
1,1-Dioxidothientan-3-yl (7-fluoro-6-(8- methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	4.1 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
Neopentyl (7-fluoro-6-(8-methyl-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	4.3 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
Tetrahydro-2H-pyran-4-yl (7-fluoro-6- (8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
MAP07	IC50	5.94 nM
2-(Methylsulfonyl)ethyl (7-fluoro-6-(8- methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	6.2 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
N-[3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluorophenyl]-2-pyrrolidin-1-ylacetamide	IC50	7.25 nM	US-9855269: Aminoquinazoline and pyridopyrimidine derivatives
(Tetrahydro-2H-pyran-2-yl)methyl (7- fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	7.5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
6-Azaspiro[3.4]octan-1-yl (7-fluoro-6- (8-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	7.5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
methyl-2,3-dihydro-1H-pyrido[2,3-	KI	8 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
2-Azabicyclo[2.2.1]heptan-5-yl (7- fluoro-6-(8-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-7- yl)isoquinolin-3-yl)carbamate	KI	8.7 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
2-(Pyridin-2-yl)ethyl (7-fluoro-6-(8- methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-7-yl)isoquinolin-3- yl)carbamate	KI	9.5 nM	US-12473301: Isoquinoline compounds for the treatment of cancer
dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-	KI	10 nM	US-12473301: Isoquinoline compounds for the treatment of cancer

ChEMBL bioactivities

1606 potent at pChembl≥5 of 1670 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	IC50	0.09	nM	CHEMBL4793665
9.46	IC50	0.348	nM	STAUROSPORINE
9.40	IC50	0.4	nM	CHEMBL4746566
9.40	Ki	0.4	nM	CHEMBL3187788
9.37	IC50	0.427	nM	STAUROSPORINE
9.24	IC50	0.57	nM	STAUROSPORINE
9.22	IC50	0.6	nM	CHEMBL4787152
9.00	IC50	1	nM	CHEMBL4759743
8.89	IC50	1.3	nM	CHEMBL4750540
8.85	IC50	1.4	nM	CHEMBL3623135
8.85	IC50	1.4	nM	CHEMBL4781045
8.85	IC50	1.4	nM	CHEMBL4783711
8.80	IC50	1.6	nM	CHEMBL3623139
8.80	Ki	1.585	nM	CHEMBL1980995
8.70	IC50	2	nM	CHEMBL4787142
8.70	IC50	2	nM	CHEMBL4779507
8.70	IC50	2	nM	CHEMBL4740167
8.68	IC50	2.1	nM	CHEMBL4745446
8.62	IC50	2.4	nM	CHEMBL4757082
8.62	IC50	2.4	nM	CHEMBL4751017
8.57	IC50	2.7	nM	CHEMBL4283353
8.54	IC50	2.9	nM	CHEMBL4777705
8.51	IC50	3.11	nM	CHEMBL5924452
8.50	Ki	3.162	nM	CHEMBL2006778
8.50	Ki	3.162	nM	CHEMBL1993648
8.50	Ki	3.162	nM	CHEMBL1970821
8.48	IC50	3.3	nM	CHEMBL5999390
8.46	IC50	3.5	nM	CHEMBL3623137
8.46	IC50	3.5	nM	CHEMBL4788172
8.46	IC50	3.5	nM	CHEMBL4800212
8.46	IC50	3.5	nM	CHEMBL4760299
8.43	IC50	3.7	nM	CHEMBL3623136
8.43	IC50	3.7	nM	CHEMBL3623138
8.43	IC50	3.7	nM	CHEMBL3754515
8.40	IC50	4	nM	CHEMBL4790042
8.40	Ki	3.981	nM	CHEMBL1988331
8.40	Ki	3.981	nM	CHEMBL2001751
8.40	Ki	3.981	nM	CHEMBL385478
8.40	Ki	3.981	nM	CHEMBL1989006
8.39	IC50	4.1	nM	CHEMBL3753424
8.34	IC50	4.6	nM	CHEMBL4778859
8.30	Ki	5.012	nM	CHEMBL1980407
8.25	IC50	5.6	nM	CHEMBL4780690
8.22	IC50	6	nM	CHEMBL4746566
8.22	IC50	6	nM	CHEMBL4741486
8.21	IC50	6.2	nM	CHEMBL5927159
8.20	Ki	6.31	nM	CHEMBL1996980
8.20	Ki	6.31	nM	CHEMBL1965836
8.20	Ki	6.31	nM	CHEMBL1992220
8.20	Ki	6.31	nM	CHEMBL2002726

PubChem BioAssay actives

342 with measured affinity, of 2130 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
5-[2-(1-ethylpiperidin-4-yl)-1,3-thiazol-5-yl]-3-(pyridin-4-ylmethoxy)pyridin-2-amine	1679419: Inhibition of human HGK using MBP as substrate assessed as residual activity by [gamma-33P]-ATP assay	ic50	0.0001	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715322: Inhibition of human HGK using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0003	uM
2-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenoxy]-2-methylpropanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0004	uM
4-[1-(2-amino-5-chloropyrimidin-4-yl)-2,3-dihydroindol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol	1894064: Inhibition of NIK (unknown origin)	ki	0.0004	uM
1-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenoxy]cyclopentane-1-carboxylic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0006	uM
(2S)-2-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenoxy]propanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0010	uM
2-[[5-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]-2-pyridinyl]oxy]-2-methylpropanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0013	uM
2-[3-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenyl]-2-methylpropanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0014	uM
(1S)-5-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]-2,3-dihydro-1H-indene-1-carboxylic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0014	uM
8-amino-N-cyclopropyl-2-(3-fluorophenyl)-1,7-naphthyridine-5-carboxamide	1250038: Inhibition of MAP4K4 (unknown origin) by Z’LYTE assay	ic50	0.0014	uM
8-amino-2-(3-fluorophenyl)-N-[1-(methylcarbamoyl)azetidin-3-yl]-1,7-naphthyridine-5-carboxamide	1250038: Inhibition of MAP4K4 (unknown origin) by Z’LYTE assay	ic50	0.0016	uM
2-[3-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenoxy]-2-methylpropanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0020	uM
2-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenoxy]acetic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0020	uM
4-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenyl]oxane-4-carboxylic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0020	uM
4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]-N-methylsulfonylbenzamide	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0021	uM
2-[[5-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]-2-pyridinyl]amino]acetic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0024	uM
4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0024	uM
4-[5-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]-2-[[(2S)-pentan-2-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexan-1-ol	1779138: Inhibition of N-terminal GST-tagged HGK (1 to 328 residues) (unknown origin) cytoplasmic domain expressed in Sf21 cells	ic50	0.0027	uM
3-(4-chlorophenyl)-5-[4-[1-(2H-tetrazol-5-yl)cyclopentyl]phenyl]pyridin-2-amine	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0029	uM
2-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenyl]-2-methylpropanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0035	uM
4-[6-amino-5-[4-(trifluoromethyl)phenyl]-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0035	uM
4-[6-amino-5-(4-methoxyphenyl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0035	uM
8-amino-2-(3-fluorophenyl)-N-(1-propanoylazetidin-3-yl)-1,7-naphthyridine-5-carboxamide	1250038: Inhibition of MAP4K4 (unknown origin) by Z’LYTE assay	ic50	0.0035	uM
5-(6-amino-3-pyridinyl)-3-(4-chlorophenyl)pyridin-2-amine	1271349: Inhibition of recombinant human MAP4K4 catalytic domain in presence of 10 uM ATP (Km) by FRET assay	ic50	0.0037	uM
8-amino-N-[1-(cyclopropanecarbonyl)azetidin-3-yl]-2-(3-fluorophenyl)-1,7-naphthyridine-5-carboxamide	1250038: Inhibition of MAP4K4 (unknown origin) by Z’LYTE assay	ic50	0.0037	uM
8-amino-2-(3-fluorophenyl)-N-(3-hydroxycyclobutyl)-1,7-naphthyridine-5-carboxamide	1250038: Inhibition of MAP4K4 (unknown origin) by Z’LYTE assay	ic50	0.0037	uM
3-(4-chlorophenyl)-5-[4-(2H-tetrazol-5-yl)phenyl]pyridin-2-amine	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0040	uM
4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]benzamide	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0041	uM
1-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenyl]cyclopentane-1-carboxylic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0046	uM
N-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenyl]sulfonylacetamide	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0056	uM
4-[6-amino-5-(4-methylphenyl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0060	uM
3-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenoxy]-2,2-dimethylpropanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0065	uM
4-[6-amino-5-(4-cyanophenyl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0072	uM
3-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0076	uM
4-[6-amino-5-(4-fluorophenyl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0076	uM
(2R)-2-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenoxy]propanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0079	uM
6-phenyl-N-pyridin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine	1188518: Inhibition of human MAP4K4 using LGRDKYKTLRQIRQ-COOH peptide substrate by LC3K assay	ic50	0.0080	uM
3-[4-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]phenyl]propanoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0081	uM
Bosutinib	624756: Binding constant for MAP4K4 kinase domain	kd	0.0082	uM
furan-3-yl-[4-(pyridin-4-ylamino)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanone	1188518: Inhibition of human MAP4K4 using LGRDKYKTLRQIRQ-COOH peptide substrate by LC3K assay	ic50	0.0100	uM
1H-pyrazol-4-yl-[4-(pyridin-4-ylamino)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methanone	1188518: Inhibition of human MAP4K4 using LGRDKYKTLRQIRQ-COOH peptide substrate by LC3K assay	ic50	0.0100	uM
4-[6-amino-5-(cyclobutylmethoxy)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0110	uM
4-[6-amino-5-(3-chlorophenyl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0110	uM
4-(6-amino-5-phenylmethoxy-3-pyridinyl)benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0110	uM
4-(6-amino-5-phenyl-3-pyridinyl)benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0120	uM
4-[6-amino-5-(4-cyanophenyl)-3-pyridinyl]-N-propan-2-ylbenzamide	1633850: Inhibition of human 6His-TEV-SHM-MAP4K4(2 to 328)-GNS expressed in baculovirus-infected sf21 cells using LRRKtide as substrate preincubated for 30 mins followed by substrate addition and measured after 75 to 90 mins by ADP-Glo Reagent based method	ic50	0.0126	uM
4-[6-amino-5-(1-methylpyrazol-4-yl)-3-pyridinyl]benzoic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0130	uM
5-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]pyrimidin-2-amine	1271349: Inhibition of recombinant human MAP4K4 catalytic domain in presence of 10 uM ATP (Km) by FRET assay	ic50	0.0149	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435910: Binding constant for MAP4K4 kinase domain	kd	0.0150	uM
(1R)-5-[6-amino-5-(4-chlorophenyl)-3-pyridinyl]-2,3-dihydro-1H-indene-1-carboxylic acid	1686984: Inhibition of recombinant human GST-tagged MAP4K4 catalytic domain (1 to 328 residues) expressed in baculovirus expression system pre-incubated for 30 mins before Ser/Thr 07 peptide substrate and 10 uM ATP addition and further incubated for 90 mins by Z’-lyte assay	ic50	0.0150	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	6
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	5
bisphenol A	increases expression, affects expression, affects methylation, affects cotreatment, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
Tobacco Smoke Pollution	increases expression, affects expression, decreases expression	3
methylmercuric chloride	increases expression	2
sodium arsenite	increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression	2
Vehicle Emissions	affects cotreatment, increases expression, increases abundance	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Formaldehyde	decreases expression, increases expression	2
Ozone	affects cotreatment, increases expression, increases abundance, affects expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression	2
FR900359	affects phosphorylation	1
moringin	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
lead acetate	increases expression	1
tributyltin	decreases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	affects localization, affects reaction, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
ochratoxin A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric chloride	increases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
mercuric bromide	increases expression	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

407 unique, capped per target: 400 binding, 5 admet, 1 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1012691	Binding	Inhibition of HGK at 5 uM	Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases. — J Med Chem
CHEMBL1964101	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: MAP4K4	PubChem BioAssay data set
CHEMBL4325215	ADMET	Inhibition of human HGK at 1 uM relative to control	Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D1NP	Abcam K-562 MAP4K4 KO	Cancer cell line	Female
CVCL_D2KA	Abcam Raji MAP4K4 KO	Cancer cell line	Male
CVCL_D7UH	Ubigene A-549 MAP4K4 KO	Cancer cell line	Male
CVCL_D9JI	Ubigene HEK293 MAP4K4 KO	Transformed cell line	Female
CVCL_E0HE	Ubigene HeLa MAP4K4 KO	Cancer cell line	Female
CVCL_SW83	HAP1 MAP4K4 (-)	Cancer cell line	Male
CVCL_UQ91	Abcam Jurkat MAP4K4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT01758211	PHASE3	UNKNOWN	Functional Magnetic Resonance Imagine(fMRI)Navigation in Intracranial Arteriovenous Malformation Surgery
NCT04297033	PHASE2	UNKNOWN	Lovastatin for Treatment of Brain Arteriovenous Malformations
NCT02314377	PHASE1	COMPLETED	Bevacizumab Therapy for Brain Arteriovenous Malformation
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06489067	Not specified	RECRUITING	Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
NCT06776380	Not specified	RECRUITING	Pubertal Development in Patients with RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07344480	Not specified	RECRUITING	Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT00883571	Not specified	COMPLETED	Comparative Study of the House Advancement Flap, Rhomboid Flap, and Y-V Anoplasty
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04710433	Not specified	COMPLETED	Non-invasive Sacral Nerve Stimulation in Children and Adolescents With Chronic Constipation
NCT04713085	Not specified	COMPLETED	Sacral Neuromodulation in Children and Adolescents
NCT04901819	Not specified	COMPLETED	Longterm Outcomes of Individuals With Anorectal Malformations
NCT05045560	Not specified	COMPLETED	Study of Antenatal and Postnatal Data of Anorectal Malformations Diagnosed at Montpellier University Hospital Over a 10-year Period (2010-2020)
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05621629	Not specified	COMPLETED	Management of FI After Surgery of ARM
NCT05749406	Not specified	UNKNOWN	Parental Attitudes to Neoanus Dilatations Post-reconstruction in Anorectal Malformations
NCT06065995	Not specified	TERMINATED	StoMakker Mobile Application
NCT06234020	Not specified	COMPLETED	Frequency of Vertebrospinal Anomalies in Patients Presenting With Anorectal Malformations
NCT06860906	Not specified	COMPLETED	V-Y Flap for Anal Stenosis
NCT07029984	Not specified	RECRUITING	Baylor Continence Scale Validity in Anorectal Malformation
NCT07099339	Not specified	COMPLETED	Effect of Pudendal Nerve Electrical Stimulation on Fecal Incontinence in Children With Repaired Anorectal Malformation
NCT07366476	Not specified	NOT_YET_RECRUITING	Effectiveness of Electrical Stimulation and Biofeedback on Fecal Incontinence in Children With Repaired Anorectal Malformation
NCT07438691	Not specified	RECRUITING	Outcomes in ARMs: Comparison Between Surgical Techniques in Patients With Perineal or Vestibular Fistula - a Multicenter Italian Study
NCT01689402	Not specified	COMPLETED	MRI for the Early Evaluation of Acute Intracerebral Hemorrhage
NCT01803685	Not specified	UNKNOWN	Nationwide Treatment Survey of Intracranial Arteriovenous Malformation in China
NCT02085278	Not specified	COMPLETED	Safety of Apollo Micro Catheter in Pediatric Patients
NCT02180958	Not specified	COMPLETED	Evaluation of ONYX in ENDOVASCULAR Treatment of Cerebral AVMs
NCT02602990	Not specified	COMPLETED	Treatment of Cerebral Arteriovenous Malformations With SQUID™ Liquid Embolic Agent
NCT02868008	Not specified	UNKNOWN	Multimodal Imaging Techniques in Assessing the Surgical Risk for Eloquent Arteriovenous Malformations
NCT03209804	Not specified	COMPLETED	Surgical Management of Cerebral Arteriovenous Malformations Within Hybrid Operation Room
NCT03367975	Not specified	UNKNOWN	NIRS Monitoring During Intracranial Interventions