MAP4K2

Summary

MAP4K2 (mitogen-activated protein kinase kinase kinase kinase 2, HGNC:6864) is a protein-coding gene on chromosome 11q13.1, encoding Mitogen-activated protein kinase kinase kinase kinase 2 (Q12851). Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.

The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is found in many tissues, its expression in lymphoid follicles is restricted to the cells of germinal centre, where it may participate in B-cell differentiation. This kinase can be activated by TNF-alpha, and has been shown to specifically activate MAP kinases. This kinase is also found to interact with TNF receptor-associated factor 2 (TRAF2), which is involved in the activation of MAP3K1/MEKK1. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5871 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 144 total — 4 pathogenic
• Druggable target: yes — 65 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004579

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6864
Approved symbol	MAP4K2
Name	mitogen-activated protein kinase kinase kinase kinase 2
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	GCK, BL44
Ensembl gene	ENSG00000168067
Ensembl biotype	protein_coding
OMIM	603166
Entrez	5871

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 10 protein_coding, 4 nonsense_mediated_decay, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000294066, ENST00000377350, ENST00000424945, ENST00000433890, ENST00000435926, ENST00000439069, ENST00000444560, ENST00000467689, ENST00000468062, ENST00000470088, ENST00000482314, ENST00000489952, ENST00000493428, ENST00000896586, ENST00000896587, ENST00000924026, ENST00000924027, ENST00000944408, ENST00000944409, ENST00000944410

RefSeq mRNA: 2 — MANE Select: NM_004579 NM_001307990, NM_004579

CCDS: CCDS8082, CCDS81582

Canonical transcript exons

ENST00000294066 — 32 exons

Exon	Start	End
ENSE00001062935	64802885	64802942
ENSE00003183914	64784918	64789624
ENSE00003459589	64789889	64789959
ENSE00003471056	64802066	64802121
ENSE00003478925	64802419	64802483
ENSE00003486486	64800764	64800826
ENSE00003491413	64797104	64797192
ENSE00003492762	64797501	64797534
ENSE00003494281	64801111	64801183
ENSE00003507715	64792172	64792275
ENSE00003525383	64801710	64801757
ENSE00003544325	64799605	64799683
ENSE00003545632	64791909	64792086
ENSE00003547102	64800311	64800392
ENSE00003552890	64789730	64789785
ENSE00003558298	64800109	64800216
ENSE00003563460	64790394	64790462
ENSE00003567017	64792364	64792422
ENSE00003575310	64797626	64797664
ENSE00003579011	64797275	64797380
ENSE00003583330	64798794	64798837
ENSE00003603515	64800900	64801031
ENSE00003621102	64790188	64790274
ENSE00003631901	64802563	64802653
ENSE00003646985	64796982	64797023
ENSE00003650095	64796809	64796893
ENSE00003658023	64796493	64796553
ENSE00003659578	64796634	64796713
ENSE00003665909	64801579	64801621
ENSE00003669091	64796273	64796390
ENSE00003790009	64799421	64799479
ENSE00003849508	64803054	64803214

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 92.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.7283 / max 133.8733, expressed in 1730 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120466	6.8257	1705
120465	0.2956	144
120467	0.2956	131
120464	0.1747	79
120463	0.1047	47
120462	0.0166	7
120461	0.0153	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	92.84	gold quality
spleen	UBERON:0002106	91.22	gold quality
right lung	UBERON:0002167	90.29	gold quality
monocyte	CL:0000576	89.87	gold quality
leukocyte	CL:0000738	89.70	gold quality
mononuclear cell	CL:0000842	89.65	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.96	gold quality
lymph node	UBERON:0000029	88.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.60	gold quality
cerebellar hemisphere	UBERON:0002245	88.54	gold quality
right frontal lobe	UBERON:0002810	88.43	gold quality
cerebellar cortex	UBERON:0002129	88.42	gold quality
upper lobe of left lung	UBERON:0008952	88.40	gold quality
prefrontal cortex	UBERON:0000451	87.79	gold quality
blood	UBERON:0000178	87.68	gold quality
apex of heart	UBERON:0002098	87.41	gold quality
cingulate cortex	UBERON:0003027	86.97	gold quality
anterior cingulate cortex	UBERON:0009835	86.89	gold quality
upper lobe of lung	UBERON:0008948	86.80	gold quality
cerebellum	UBERON:0002037	86.34	gold quality
body of stomach	UBERON:0001161	85.64	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.63	gold quality
amygdala	UBERON:0001876	85.34	gold quality
right lobe of thyroid gland	UBERON:0001119	85.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.18	gold quality
left lobe of thyroid gland	UBERON:0001120	84.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.14	gold quality
stomach	UBERON:0000945	83.87	gold quality
mucosa of transverse colon	UBERON:0004991	83.75	gold quality
thyroid gland	UBERON:0002046	83.65	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.71
E-MTAB-2983	no	21.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting MAP4K2, 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-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895

Literature-anchored findings (GeneRIF, showing 7)

• CCM3 is located on the Golgi apparatus, forming a complex with proteins of the germinal center kinase III (GCKIII) family and GM130, a Golgi-resident protein. (PMID:20332113)
• Data suggest that the Rabin8-Rab8-Sec15 interaction may couple the activation of Rab8 to the recruitment of the Rab8 effector and is involved in the regulation of vesicular trafficking for primary cilium formation. (PMID:22433857)
• Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB. (PMID:24072714)
• Data indicate 4-substituted 1H-pyrrolo[2,3-b]pyridines as potent inhibitors against TGFbeta-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2). (PMID:25075558)
• These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. (PMID:27151888)
• MAP4K2 was up-regulated and its expression was inversely correlated with collagen expression in the osteoblasts from older donors. (PMID:30217450)
• MAP4K2 connects the Hippo pathway to autophagy in response to energy stress. (PMID:37937799)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Map4k2	ENSMUSG00000024948
rattus_norvegicus	Map4k2	ENSRNOG00000021061

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), 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), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase kinase 2 — Q12851 (reviewed: Q12851)

Alternative names: B lymphocyte serine/threonine-protein kinase, Germinal center kinase, MAPK/ERK kinase kinase kinase 2, Rab8-interacting protein

All UniProt accessions (5): C9JCU6, Q12851, F2Z2B3, F8WCP4, H7C208

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Also mediates the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion. 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.

Subunit / interactions. Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with RAB8A.

Subcellular location. Cytoplasm. Basolateral cell membrane. Golgi apparatus membrane.

Tissue specificity. Highly expressed in germinal center but not mantle zone B-cells. Also expressed in lung, brain and placenta and at lower levels in other tissues examined.

Post-translational modifications. Polyubiquitinated through ‘Lys-48’-polyubiquitin chains, allowing proteasomal turnover. Ubiquitination requires the kinase activity of MAP4K2/GCK. Autophosphorylated in response to tumor necrosis factor (TNF), endotoxins or pro-inflammatory stimuli. Autophosphorylation leads to activation.

Activity regulation. The tumor necrosis factor (TNF), as well as endotoxins and pro-inflammatory stimuli such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), peptidoglycan (PGN), flagellin, or lipid A activate MAP4K2 by promoting its autophosphorylation.

Domain organisation. The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains. Proteins with PEST domains are frequently targets of degradation by the ubiquitin proteasome.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q12851-1	1	yes
Q12851-2	2

RefSeq proteins (2): NP_001294919, NP_004570* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001180	CNH_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR021160	MAPKKKK	Family
IPR050629	STE20/SPS1-PAK	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 (15 total): region of interest 4, domain 2, binding site 2, modified residue 2, chain 1, splice variant 1, sequence conflict 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12851-F1	75.32	0.36

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): 136 (proton acceptor)

Ligand- & substrate-binding residues (2): 45; 22–30

Post-translational modifications (2): 328, 394

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 600 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, BIOCARTA_MAL_PATHWAY, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_VESICLE_LOCALIZATION, PID_HNF3B_PATHWAY, GOBP_NADPPLUS_METABOLIC_PROCESS, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (9): protein phosphorylation (GO:0006468), obsolete vesicle targeting (GO:0006903), immune response (GO:0006955), JNK cascade (GO:0007254), intracellular signal transduction (GO:0035556), positive regulation of JUN kinase activity (GO:0043507), innate immune response (GO:0045087), positive regulation of JNK cascade (GO:0046330), immune system process (GO:0002376)

GO Molecular Function (10): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), MAP kinase kinase kinase kinase activity (GO:0008349), mitogen-activated protein kinase kinase kinase binding (GO:0031435), 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 (6): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), basolateral plasma membrane (GO:0016323), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	2
intracellular anatomical structure	2
protein kinase activity	2
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
immune system process	1
response to stimulus	1
signal transduction	1
JUN kinase activity	1
positive regulation of MAP kinase activity	1
regulation of JUN kinase activity	1
immune response	1
defense response to symbiont	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
biological_process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein serine/threonine kinase activity	1
protein kinase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
basal plasma membrane	1
plasma membrane region	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

820 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP4K2	PDCD10	Q9BUL8	765
MAP4K2	PHF12	Q96QT6	728
MAP4K2	STRIP1	Q5VSL9	722
MAP4K2	STRN	O43815	720
MAP4K2	STRN4	Q9NRL3	700
MAP4K2	RAB8A	P24407	647
MAP4K2	SLMAP	Q14BN4	596
MAP4K2	MAP3K1	Q13233	578
MAP4K2	GABARAP	O95166	485
MAP4K2	MOB4	Q9Y3A3	480
MAP4K2	MRPL11	Q9Y3B7	475
MAP4K2	MBP	P02686	474
MAP4K2	SNRPB2	P08579	473
MAP4K2	CDC42	P21181	448
MAP4K2	CCM2	Q9BSQ5	446

IntAct

42 interactions, top by confidence:

A	B	Type	Score
DPYSL4	PLCG1	psi-mi:“MI:0914”(association)	0.530
POT1	MAP4K2	psi-mi:“MI:0915”(physical association)	0.510
MAP4K2	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MAP3K1	MAP4K2	psi-mi:“MI:0915”(physical association)	0.400
MAP4K2	Map3k1	psi-mi:“MI:0915”(physical association)	0.400
MAP4K2	MAP3K11	psi-mi:“MI:0915”(physical association)	0.400
MAP4K2	MAP3K1	psi-mi:“MI:0915”(physical association)	0.400
MAP4K2	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
DEFB1	MAP4K2	psi-mi:“MI:0915”(physical association)	0.370
HNRNPA2B1	MAP4K2	psi-mi:“MI:0915”(physical association)	0.370
NACAD	MAP4K2	psi-mi:“MI:0915”(physical association)	0.370
PRDX4	MAP4K2	psi-mi:“MI:0915”(physical association)	0.370
SERPINA4	MAP4K2	psi-mi:“MI:0915”(physical association)	0.370
MAP4K2	SNRNP35	psi-mi:“MI:0915”(physical association)	0.370
XRCC6	MAP4K2	psi-mi:“MI:0915”(physical association)	0.370
JUN		psi-mi:“MI:0914”(association)	0.350
	SGK1	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AHRR	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
STK3	MYO1C	psi-mi:“MI:0914”(association)	0.350
CDKL2	MYO1C	psi-mi:“MI:0914”(association)	0.350
SRPK1	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
NAA30	HARS2	psi-mi:“MI:0914”(association)	0.350
CDC37	MAP2K7	psi-mi:“MI:0914”(association)	0.350
NAA30	ATP1A3	psi-mi:“MI:0914”(association)	0.350
NAA30	PAPSS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (111): MAP3K1 (Reconstituted Complex), MAP2K4 (Reconstituted Complex), TRAF2 (Reconstituted Complex), TRAF2 (Affinity Capture-Western), MAP4K2 (Two-hybrid), MAP4K2 (Affinity Capture-Western), MAP4K2 (Co-fractionation), LATS1 (Biochemical Activity), MAP4K2 (Reconstituted Complex), MAP4K2 (Reconstituted Complex), MAP4K2 (Reconstituted Complex), MAP4K2 (Reconstituted Complex), RPL13AP3 (Affinity Capture-MS), GABARAPL2 (Affinity Capture-MS), GABARAP (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A0A1L8HX76, A6QR40, O08764, O60294, O95382, P10938, P70218, P97452, Q12851, Q14137, Q15334, Q16586, Q28686, Q32P44, Q3TJ91, Q499N3, Q499U2, Q4KLI9, Q561R2, Q562C2, Q5RBH8, Q5RCX2, Q61161, Q6AY79, Q6F5E8, Q6P1M3, Q6V7V2, Q7SZE3, Q7TMC8, Q80Y17, Q8BYZ7, Q8C3I8, Q8C6B2, Q8CHW4, Q8K4K5, Q8MKF0, Q8N0W3, Q8VC03, Q91WI7

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

5 interactions.

A	Effect	B	Mechanism
MAP4K2	“up-regulates activity”	MAP4K2	phosphorylation
MAP4K2	up-regulates	MAP3K1	binding
TRAF2	up-regulates	MAP4K2	binding
MAPK8IP1	down-regulates	MAP4K2	binding
MAP4K2	“up-regulates activity”	PSMD2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 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	6	9.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	109
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3244552	NC_000011.9:g.(?64567607)(64572007_?)del	Pathogenic
3244553	NC_000011.9:g.(?64570260)(64572077_?)del	Pathogenic
3244557	NC_000011.9:g.(?64550219)(64573119_?)del	Pathogenic
428084	NM_001370259.2(MEN1):c.625del (p.Gln209fs)	Pathogenic

SpliceAI

3946 predictions. Top by Δscore:

Variant	Effect	Δscore
11:64789787:T:A	acceptor_loss	1.0000
11:64789958:CA:C	acceptor_gain	1.0000
11:64789960:C:CC	acceptor_gain	1.0000
11:64790181:CACT:C	donor_loss	1.0000
11:64790182:A:AC	donor_gain	1.0000
11:64790182:ACTC:A	donor_loss	1.0000
11:64790183:C:CC	donor_gain	1.0000
11:64790184:T:TC	donor_loss	1.0000
11:64790185:C:CC	donor_loss	1.0000
11:64790186:A:AC	donor_gain	1.0000
11:64790186:AC:A	donor_gain	1.0000
11:64790187:C:A	donor_loss	1.0000
11:64790187:C:CC	donor_gain	1.0000
11:64790187:CC:C	donor_gain	1.0000
11:64790187:CCCA:C	donor_gain	1.0000
11:64790271:CAGC:C	acceptor_gain	1.0000
11:64790272:AGC:A	acceptor_gain	1.0000
11:64790273:GC:G	acceptor_gain	1.0000
11:64790273:GCC:G	acceptor_loss	1.0000
11:64790274:CC:C	acceptor_gain	1.0000
11:64790275:C:CC	acceptor_gain	1.0000
11:64790275:CTGCA:C	acceptor_loss	1.0000
11:64790278:C:CT	acceptor_gain	1.0000
11:64790392:A:AC	donor_gain	1.0000
11:64790393:C:CC	donor_gain	1.0000
11:64790460:CCT:C	acceptor_gain	1.0000
11:64790461:CT:C	acceptor_gain	1.0000
11:64790461:CTC:C	acceptor_gain	1.0000
11:64790462:TCT:T	acceptor_gain	1.0000
11:64790463:C:CC	acceptor_gain	1.0000

AlphaMissense

5309 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:64789920:C:T	G763E	1.000
11:64789938:A:G	L757P	1.000
11:64800335:C:A	R261S	1.000
11:64800335:C:G	R261S	1.000
11:64800336:C:A	R261M	1.000
11:64800336:C:G	R261T	1.000
11:64800357:A:G	L254P	1.000
11:64800942:A:G	L207P	1.000
11:64800952:C:G	A204P	1.000
11:64800960:C:T	G201D	1.000
11:64800961:C:G	G201R	1.000
11:64800968:C:A	W198C	1.000
11:64800968:C:G	W198C	1.000
11:64800970:A:G	W198R	1.000
11:64800970:A:T	W198R	1.000
11:64800975:T:A	D196V	1.000
11:64800976:C:A	D196Y	1.000
11:64800976:C:G	D196H	1.000
11:64800977:A:C	C195W	1.000
11:64800978:C:T	C195Y	1.000
11:64801029:A:C	M178R	1.000
11:64801029:A:G	M178T	1.000
11:64801031:C:A	W177C	1.000
11:64801031:C:G	W177C	1.000
11:64801112:A:G	W177R	1.000
11:64801112:A:T	W177R	1.000
11:64801117:G:T	P175H	1.000
11:64801123:C:T	G173E	1.000
11:64801124:C:A	G173W	1.000
11:64801124:C:G	G173R	1.000

dbSNP variants (sampled 300 via entrez): RS1000096469 (11:64784913 G>A), RS1000220505 (11:64794169 CA>C), RS1000953853 (11:64801295 G>A), RS1001186513 (11:64800575 C>T), RS1001373483 (11:64785547 T>C), RS1001425274 (11:64800478 A>G), RS1001701928 (11:64794561 T>C), RS1001719864 (11:64785336 T>A), RS1001834841 (11:64790355 A>G), RS1002202336 (11:64802383 G>A), RS1002241090 (11:64801912 C>G,T), RS1002327748 (11:64796181 A>C,G), RS1002459844 (11:64791085 G>A), RS1002540892 (11:64804238 C>T), RS1002689514 (11:64798136 C>T)

Disease associations

OMIM: gene MIM:603166 | disease phenotypes: MIM:131100

GenCC curated gene-disease

Mondo (2): multiple endocrine neoplasia type 1 (MONDO:0007540), hereditary neoplastic syndrome (MONDO:0015356)

Orphanet (2): Multiple endocrine neoplasia type 1 (Orphanet:652), Inherited cancer-predisposing syndrome (Orphanet:140162)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001163_1	Urate levels	2.000000e-17
GCST001163_5	Urate levels	6.000000e-11
GCST010512_13	Serum uric acid levels	3.000000e-52

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004761	uric acid measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018761	Multiple Endocrine Neoplasia Type 1	C04.588.322.400.500; C04.651.600.500; C04.700.630.500; C16.320.700.630.500; C19.344.400.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5330 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

65 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 269,511 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289494	TIVOZANIB	4	4,455
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2103743	TOFACITINIB CITRATE	4	1,672
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4
CHEMBL1091644	LINSITINIB	3
CHEMBL1879463	DACTOLISIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL274654	ORANTINIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL428690	ALVOCIDIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL603469	LESTAURTINIB	3

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — KHS subfamily

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
belizatinib	Inhibition	7.96	pKd
BAY 61-3606	Inhibition	7.95	pIC50
NG-25	Inhibition	7.66	pIC50

Binding affinities (BindingDB)

178 measured of 190 human assays (199 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5705826	IC50	27 nM
2-[[3-(4-ethylphenyl)-1-phenyl-pyrazol-4-yl]methyl]isothiourea;hydrochloride	EC50	39.9 nM
(2Z)-1-methyl-2-[(2Z)-2-[(1-methyl-2-benzo[e][1,3]benzothiazol-1-iumyl)methylidene]butylidene]benzo[e][1,3]benzothiazole;chloride	EC50	140 nM
MLS000911514	EC50	340 nM
YW-SI	EC50	520 nM
(5Z)-3-butyl-5-[(2E,4E)-5-phenylazanylpenta-2,4-dienylidene]-2-sulfanylidene-1,3-thiazolidin-4-one	EC50	576 nM
2-amino-4-[4-(4-chlorobenzyl)oxy-3-methoxy-phenyl]-6-phenyl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester	EC50	580 nM
3,4,5-trihydroxybenzoic acid [(3R,4S,5S,6S)-3,4,5,6-tetragalloyloxytetrahydropyran-2-yl]methyl ester	EC50	951 nM
SMR000391146	EC50	1010 nM
1-Decyloxycarbonylmethyl-3-methyl-2-o-tolyloxymethyl-3H-benzoimidazol-1-ium	EC50	1020 nM
2-[[2-[2-(dimethylamino)ethylamino]-1-oxoethyl]amino]-4-(4-phenylphenyl)-3-thiophenecarboxylic acid ethyl ester;hydrochloride	EC50	1090 nM
6-(3-ethoxyphenyl)-3-thiophen-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole	EC50	1100 nM
3-(4-fluorophenyl)-7,8-dimethoxy-5-[(4-methoxyphenyl)methyl]pyrazolo[4,3-c]quinoline	EC50	1150 nM
LW-LW	EC50	1440 nM
3-amino-5-(4-methoxyphenyl)-1,5-dihydro-6H-pyrazolo[4,3-c]pyridazin-6-one	EC50	1480 nM
(5S)-4-[2-(3,4-dichlorophenyl)ethyl]-1-[(1R)-5-[methyl(p-anisyl)amino]-1-[(p-anisylamino)methyl]pentyl]-5-phenyl-piperazine-2,3-quinone	EC50	1480 nM
SMR000391068	EC50	1750 nM
(2Z)-3-ethyl-2-[(1-ethyl-6,8-dimethyl-2-quinolin-1-iumyl)methylidene]-6-methyl-1,3-benzothiazole;iodide	EC50	1770 nM
1-Decyloxycarbonylmethyl-3-methyl-2-p-tolyloxymethyl-3H-benzoimidazol-1-ium	EC50	1800 nM
2-[[4-(2,4-dichlorobenzyl)oxybenzylidene]amino]guanidine	EC50	1910 nM
4-[(6-chloranyl-2-methoxy-acridin-9-yl)amino]-5-methyl-2-propan-2-yl-phenol	EC50	1940 nM
(6-bromo-2-methyl-4-quinolyl)-(p-anisylideneamino)amine	EC50	1940 nM
MLS000589651	EC50	1950 nM
3-(3-chloro-4-methoxybenzyl)-6,7-dimethoxy-2-[(4-methylbenzyl)sulfanyl]-4(3H)-quinazolinimine	EC50	1970 nM
(2R,3R)-1-N,3-dimethyl-2-N-[(2R)-3-naphthalen-1-yl-2-[2-[3-(trifluoromethyl)phenyl]ethylamino]propyl]pentane-1,2-diamine	EC50	2030 nM
(5Z)-5-{[5-(4-fluorophenyl)furan-2-yl]methylidene}-3-(prop-2-en-1-yl)-2-sulfanylidene-1,3-thiazolidin-4-one	EC50	2060 nM
MLS001165417	EC50	2240 nM
5-(4-chlorophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-furancarboxamide	EC50	2260 nM
2-amino-4-[4-(4-carbomethoxybenzyl)oxyphenyl]-6-phenyl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester	EC50	2380 nM
2-[3-methyl-2-(phenoxymethyl)-1-benzimidazol-3-iumyl]acetic acid decyl ester;chloride	EC50	2600 nM
(2Z)-3-ethyl-2-[(1-ethyl-6-methyl-2-quinolin-1-iumyl)methylidene]-5,6-dimethyl-1,3-benzothiazole;iodide	EC50	2630 nM
(5E)-5-[(2Z)-2-(3-ethyl-1,3-benzothiazol-2-ylidene)ethylidene]-3-propyl-2-sulfanylidene-1,3-thiazolidin-4-one	EC50	2670 nM
SMR000391064	EC50	2690 nM
5-(3-bromanyl-4-methoxy-phenyl)-N-(4-ethylphenyl)-4-phenyl-1,3,4-thiadiazol-4-ium-2-amine;chloride	EC50	2850 nM
5-bromanyl-N-[2-(2-methylindol-1-yl)ethyl]furan-2-carboxamide	EC50	2920 nM
MLS001004803	EC50	3130 nM
(5Z)-5-[(2Z)-2-(3-ethyl-4,5-diphenyl-1,3-thiazol-2-ylidene)ethylidene]-3-methyl-2-sulfanylidene-1,3-thiazolidin-4-one	EC50	3350 nM
3-amino-6-methyl-7-thiazolo[3,2-b][1,2,4]triazinone	EC50	3400 nM
2,6,7-Trihydroxy-9-methyl-xanthen-3-one	IC50	3600 nM
4-methyl-5-[2-(2-pyrimidinylamino)-4-thiazolyl]-2-thiazolamine	IC50	3690 nM
2-[4-(2,5-dimethylphenyl)-1-piperazinyl]-6,7-dimethoxy-4-quinazolinamine;hydrochloride	EC50	3890 nM
MLS000080844	EC50	4050 nM
(2S)-6-amino-2-[4-[3-[1-[(1S)-1-(1H-indol-3-ylmethyl)-2-keto-2-methoxy-ethyl]triazol-4-yl]-5-(piperazine-1-carbonyl)phenyl]triazol-1-yl]hexanoic acid methyl ester;hydrochloride	EC50	4440 nM
MLS000101692	IC50	4570 nM
2-(2,7-dipropoxy-9H-fluoren-9-ylidene)hydrazinecarboximidamide	EC50	4590 nM
2-(diethylamino)ethyl 4-[[(Z)-2-cyano-2-[4-(2-oxidanylidenechromen-3-yl)-1,3-thiazol-2-yl]ethenyl]amino]benzoate	EC50	4880 nM
4-[(4-methylphenyl)methyl]-N-[1-(phenylmethyl)-4-piperidinyl]-2,3-dihydro-1,4-benzothiazine-6-carboxamide	EC50	4920 nM
MLS001017289	EC50	5010 nM
5-(2-bromanyl-4,5-dimethoxy-phenyl)-N-(4-ethylphenyl)-4-phenyl-1,3,4-thiadiazol-4-ium-2-amine;chloride	EC50	5060 nM
2,6-bis(iodanyl)-4-[2-(1,3,3-trimethylindol-2-ylidene)ethenyl]phenol	EC50	5140 nM

ChEMBL bioactivities

608 potent at pChembl≥5 of 640 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.32	IC50	0.481	nM	STAUROSPORINE
9.00	IC50	1	nM	CHEMBL4214342
8.89	IC50	1.3	nM	CHEMBL5999390
8.70	IC50	2	nM	CHEMBL4202685
8.70	IC50	2	nM	CHEMBL4207036
8.70	Ki	1.995	nM	CHEMBL1994669
8.51	Kd	3.1	nM	BOSUTINIB
8.50	Ki	3.162	nM	CHEMBL244378
8.50	Ki	3.162	nM	CHEMBL1984548
8.40	IC50	4	nM	CERDULATINIB
8.33	Kd	4.7	nM	LESTAURTINIB
8.30	IC50	5	nM	CHEMBL4213673
8.30	IC50	5	nM	CHEMBL4207100
8.30	Ki	5.012	nM	CHEMBL1997129
8.30	Ki	5.012	nM	CHEMBL1980995
8.30	Ki	5.012	nM	CENISERTIB
8.30	Ki	5.012	nM	CHEMBL396523
8.22	IC50	6	nM	CHEMBL4217421
8.22	Kd	6	nM	CHEMBL4465866
8.15	IC50	7	nM	CHEMBL4214863
8.15	Kd	7	nM	CHEMBL4576489
8.10	IC50	8	nM	CHEMBL1214141
8.10	IC50	8	nM	CHEMBL4209948
8.10	IC50	8	nM	CHEMBL4207753
8.10	Ki	7.943	nM	CHEMBL1241473
8.10	Ki	7.943	nM	CHEMBL1973540
8.10	Ki	7.943	nM	CHEMBL1991674
8.10	Ki	7.943	nM	ILORASERTIB
8.06	Kd	8.8	nM	STAUROSPORINE
8.00	IC50	10	nM	CHEMBL4211976
8.00	IC50	9.9	nM	BOSUTINIB
8.00	Ki	10	nM	CHEMBL1971029
7.96	Kd	11	nM	CHEMBL2172308
7.96	Kd	11	nM	KW-2449
7.92	Kd	11.88	nM	CHEMBL3752910
7.90	Ki	12.59	nM	CHEMBL1970142
7.90	Ki	12.59	nM	CHEMBL1983575
7.86	Kd	13.94	nM	CHEMBL5653589
7.85	IC50	14	nM	CHEMBL4213019
7.80	IC50	16	nM	CHEMBL4216786
7.80	Ki	15.85	nM	CHEMBL1980407
7.80	Ki	15.85	nM	CHEMBL1988163
7.80	Ki	15.85	nM	CHEMBL1190711
7.80	Ki	15.85	nM	CHEMBL1986855
7.77	IC50	17	nM	CHEMBL4212663
7.74	IC50	18.2	nM	CHEMBL5705830
7.70	ED50	20.14	nM	CHEMBL3752910
7.70	IC50	19.8	nM	CHEMBL5705844
7.70	Ki	19.95	nM	CHEMBL1986263
7.70	Ki	19.95	nM	CHEMBL1974328

PubChem BioAssay actives

163 with measured affinity, of 1975 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	2198250: Inhibition of human GCK 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	0.0005	uM
N-[3-[7-[[6-(4-acetylpiperazin-1-yl)-3-pyridinyl]amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0010	uM
N-[3-[7-[[6-(4-ethylpiperazine-1-carbonyl)-3-pyridinyl]amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0020	uM
4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0020	uM
Bosutinib	624959: Binding constant for MAP4K2 kinase domain	kd	0.0031	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	1993900: Inhibition of GCK (unknown origin)	ic50	0.0040	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	507601: Binding affinity to MAP4K2	kd	0.0047	uM
N-[3-[7-[(2,5-dimethylpyrazol-3-yl)amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0050	uM
N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0050	uM
N-[4-methyl-3-[1-methyl-7-[(1-methylpyrazol-4-yl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0060	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	1526221: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged MAP4K2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0060	uM
N-[3-[7-[[6-(4-ethylpiperazin-1-yl)-3-pyridinyl]amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0070	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	1526221: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged MAP4K2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0070	uM
N-[3-[7-[4-(4-ethylpiperazin-1-yl)anilino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0080	uM
N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0080	uM
4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[1-methyl-7-[(1-methylpyrazol-4-yl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0080	uM
N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0100	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624959: Binding constant for MAP4K2 kinase domain	kd	0.0110	uM
4-fluoro-N-[6-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-1-[4-(propan-2-ylcarbamoyl)cyclohexyl]benzimidazol-2-yl]benzamide	703115: Binding affinity to human MAP4K2 by Ambit titration assay	kd	0.0110	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148698: Binding affinity to human MAP4K2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0119	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148698: Binding affinity to human MAP4K2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0139	uM
4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[3-[7-[[6-(4-ethylpiperazine-1-carbonyl)-3-pyridinyl]amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0140	uM
N-[3-[7-[[6-(4-acetylpiperazin-1-yl)-3-pyridinyl]amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0160	uM
4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[3-[7-[(2,5-dimethylpyrazol-3-yl)amino]-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0170	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-[(6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]benzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0182	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)benzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0198	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl]-4-methylbenzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0206	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0217	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0238	uM
N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-4-pyrrol-1-yl-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0240	uM
46179972	446601: Inhibition of GCK	ic50	0.0240	uM
3,5-difluoro-N-[6-[[4-(2-hydroxypropan-2-yl)piperidin-1-yl]methyl]-1-[4-(propan-2-ylcarbamoyl)cyclohexyl]benzimidazol-2-yl]benzamide	703115: Binding affinity to human MAP4K2 by Ambit titration assay	kd	0.0250	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-[2-(methylamino)pyrimidin-4-yl]oxybenzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0265	uM
3-(4-methylimidazol-1-yl)-N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-5-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0270	uM
N-[3-(7-amino-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0280	uM
4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0301	uM
3-(6,7-dimethoxyquinazolin-4-yl)oxy-N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methylbenzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0305	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-[6-(methylamino)pyrimidin-4-yl]oxybenzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0306	uM
N-[3-[7-(2-hydroxyethylamino)-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0330	uM
Sunitinib	624959: Binding constant for MAP4K2 kinase domain	kd	0.0330	uM
N-[3-[1-ethyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-4-methyl-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0340	uM
4-methyl-3-[6-(methylamino)pyrimidin-4-yl]oxy-N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]benzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0372	uM
4-methyl-N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0390	uM
N-[2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-(2-methyl-3-pyridinyl)phenyl]-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide	1922872: Inhibition of MAP4K2 (unknown origin) incubated for 90 mins in presence of ATP by microplate reader assay	ic50	0.0400	uM
Ponatinib	1425052: 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	0.0410	uM
N-[3-[7-(cyclopropylamino)-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0420	uM
N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl-3-(1H-pyrazolo[5,4-d]pyrimidin-4-yloxy)benzamide	2180110: Inhibition of MAP4K2 (unknown origin) Lys1 labeling site by KiNativ Profiling analysis	ic50	0.0438	uM
N-[4-methyl-3-[1-methyl-7-[(6-methyl-3-pyridinyl)amino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-morpholin-4-yl-5-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0450	uM
N-[3-(7-anilino-1-methyl-2-oxo-4H-pyrimido[4,5-d]pyrimidin-3-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	1386319: Inhibition of GCK (unknown origin) by radiometric biochemical kinase assay	ic50	0.0470	uM
2-[[7-(1,3-benzodioxol-5-yl)imidazo[1,2-c]pyrimidin-5-yl]amino]pyridine-3-carboxamide	1456670: Binding affinity to human wild type GCK (M1 to G318 residues) expressed in mammalian expression system by KINOMEScan assay	kd	0.0490	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases expression, affects expression, increases abundance	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Tunicamycin	decreases expression, increases expression	2
Valproic Acid	increases expression, increases methylation	2
1-Methyl-4-phenylpyridinium	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
AZ-628	affects cotreatment, affects response to substance	1
FR900359	affects phosphorylation	1
takinib	decreases activity	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	decreases reaction, affects expression	1
beta-lapachone	decreases expression	1
cypermethrin	increases expression	1
sodium arsenite	affects expression	1
benzo(e)pyrene	increases methylation	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide	decreases activity	1
abrine	decreases expression	1
jinfukang	affects cotreatment, 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	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Allergens	affects cotreatment, increases expression	1
Vehicle Emissions	increases expression, affects cotreatment	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, decreases expression	1
Caffeine	increases phosphorylation	1

ChEMBL screening assays

292 unique, capped per target: 291 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1042397	Binding	Inhibition of GCK	Janus kinase 2 inhibitors. Synthesis and characterization of a novel polycyclic azaindole. — J Med Chem
CHEMBL1963772	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: MAP4K2	PubChem BioAssay data set

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D7UF	Ubigene A-549 MAP4K2 KO	Cancer cell line	Male
CVCL_D9JH	Ubigene HEK293 MAP4K2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001277	PHASE2	COMPLETED	Studies of Elevated Parathyroid Activity
NCT00454363	PHASE2	COMPLETED	Pazopanib Hydrochloride in Treating Patients With Advanced Neuroendocrine Cancer
NCT02101918	PHASE2	COMPLETED	Ziv-Aflibercept in Treating and Computed Tomography Perfusion Imaging in Predicting Response in Patients With Pancreatic Neuroendocrine Tumors That Are Metastatic or Cannot Be Removed by Surgery
NCT03950609	PHASE2	ACTIVE_NOT_RECRUITING	Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Carcinoid Tumors
NCT02831179	PHASE1	WITHDRAWN	Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
NCT03001349	EARLY_PHASE1	TERMINATED	68Ga-DOTA-TOC PET/CT in Imaging Participants With Neuroendocrine Tumors
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01794676	Not specified	COMPLETED	Genetic Evaluation of Families With Endocrine Cancers
NCT03043508	Not specified	UNKNOWN	Overall and Disease Specific Survival in Patients With Confirmed MEN1 With or Without PNET (Pancreatic Neuroendocrine Tumors)
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03966612	Not specified	RECRUITING	Study and Monitoring of Multiple Endocrine Neoplasia Type 1
NCT05037461	Not specified	RECRUITING	Precision Radiotherapy Using MR-linac for Pancreatic Neuroendocrine Tumours in MEN1 Patients
NCT05061784	Not specified	COMPLETED	Routine Transcervical Thymectomy in MEN-1 Patients
NCT05554744	Not specified	UNKNOWN	EUS-FNI for MEN1-related Pancreatic Neuroendocrine Tumors
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT06790251	Not specified	NOT_YET_RECRUITING	Institution of an Italian Multicenter Database of Patients With Multiple Endocrine Neoplasia Type 1 (MENNET1 Database)
NCT07272187	Not specified	RECRUITING	Endoscopic Ultrasound-guided Radiofrequency Ablation for Upper Gastrointestinal Tract Lesions
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing
NCT05562778	Not specified	RECRUITING	Chatbot to Maximize Hereditary Cancer Genetic Risk Assessment
NCT05664867	Not specified	RECRUITING	Implementation of Population Cancer Genetic Services in Federally Qualified Health Centers (FQHC)
NCT05721326	Not specified	COMPLETED	Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
NCT06096688	Not specified	RECRUITING	Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction
NCT06654466	Not specified	RECRUITING	Closing the GAPS: Guideline Adherence, Prevention and Surveillance in Hereditary Cancer
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06726642	Not specified	RECRUITING	CfDNA in Hereditary And High-risk Malignancies 2
NCT06914726	Not specified	ENROLLING_BY_INVITATION	Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes
NCT06927947	Not specified	RECRUITING	Navigation Interventions to Improve Cascade Genetic Testing Among Relatives of Patients With Hereditary Cancer Syndromes