CAMK4

Summary

CAMK4 (calcium/calmodulin dependent protein kinase IV, HGNC:1464) is a protein-coding gene on chromosome 5q22.1, encoding Calcium/calmodulin-dependent protein kinase type IV (Q16566). Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune res….

The product of this gene belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. This enzyme is a multifunctional serine/threonine protein kinase with limited tissue distribution, that has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells.

Source: NCBI Gene 814 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 27
• Clinical variants (ClinVar): 111 total — 2 pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 14 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001744

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1464
Approved symbol	CAMK4
Name	calcium/calmodulin dependent protein kinase IV
Location	5q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CaMK-GR, CaMKIV
Ensembl gene	ENSG00000152495
Ensembl biotype	protein_coding
OMIM	114080
Entrez	814

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 6 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000282356, ENST00000502916, ENST00000504090, ENST00000504544, ENST00000505763, ENST00000508074, ENST00000509408, ENST00000509645, ENST00000510858, ENST00000512453, ENST00000512890, ENST00000514007, ENST00000515231, ENST00000885363, ENST00000885364, ENST00000885365, ENST00000911803, ENST00000955457

RefSeq mRNA: 5 — MANE Select: NM_001744 NM_001323374, NM_001323375, NM_001323376, NM_001323377, NM_001744

CCDS: CCDS4103

Canonical transcript exons

ENST00000282356 — 11 exons

Exon	Start	End
ENSE00001264019	111484026	111494886
ENSE00002032738	111224384	111224644
ENSE00003473567	111446686	111446776
ENSE00003491780	111374850	111374912
ENSE00003494943	111376860	111376942
ENSE00003502511	111394710	111394782
ENSE00003522252	111473311	111473386
ENSE00003540205	111482785	111482937
ENSE00003586531	111344024	111344102
ENSE00003639159	111449129	111449203
ENSE00003667531	111478381	111478507

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 95.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.1644 / max 875.7412, expressed in 1177 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57972	13.9091	1132
57973	2.6519	321
57975	0.9304	174
57970	0.6424	150
57974	0.4688	124
57976	0.3861	99
57971	0.3635	157
57966	0.2492	88
57969	0.2490	92
57967	0.1591	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	95.24	gold quality
cerebellar cortex	UBERON:0002129	94.69	gold quality
cerebellar hemisphere	UBERON:0002245	94.61	gold quality
cerebellum	UBERON:0002037	94.17	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.86	gold quality
cortical plate	UBERON:0005343	90.29	gold quality
middle temporal gyrus	UBERON:0002771	90.05	gold quality
left testis	UBERON:0004533	90.01	gold quality
right testis	UBERON:0004534	89.26	gold quality
paraflocculus	UBERON:0005351	87.65	gold quality
ganglionic eminence	UBERON:0004023	87.59	gold quality
nucleus accumbens	UBERON:0001882	87.03	gold quality
testis	UBERON:0000473	87.01	gold quality
superior frontal gyrus	UBERON:0002661	86.85	gold quality
lateral globus pallidus	UBERON:0002476	86.54	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.29	gold quality
entorhinal cortex	UBERON:0002728	85.99	gold quality
prefrontal cortex	UBERON:0000451	85.75	gold quality
postcentral gyrus	UBERON:0002581	85.73	gold quality
pons	UBERON:0000988	85.56	gold quality
caudate nucleus	UBERON:0001873	85.34	gold quality
parietal lobe	UBERON:0001872	85.32	gold quality
frontal pole	UBERON:0002795	84.77	gold quality
putamen	UBERON:0001874	83.90	gold quality
primary visual cortex	UBERON:0002436	83.77	gold quality
frontal cortex	UBERON:0001870	83.01	gold quality
occipital lobe	UBERON:0002021	82.89	gold quality
secondary oocyte	CL:0000655	82.22	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.09	gold quality
neocortex	UBERON:0001950	81.94	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	98.37
E-CURD-122	yes	44.83
E-HCAD-10	yes	21.36
E-ANND-3	yes	9.69
E-CURD-112	yes	6.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREM, EZH2, IRF1, IRF2, MEF2A, NR2F1, PRDM1, RELA, TBP, TP53

miRNA regulators (miRDB)

383 targeting CAMK4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4476	100.00	68.18	2030
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-6876-5P	100.00	67.68	2126
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-1277-5P	100.00	73.95	5056
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-33A-5P	99.99	68.62	1055

Literature-anchored findings (GeneRIF, showing 40)

• CaMKIV proteins were found in the nucleus of epithelial ovarian cancer tissue. CaMKIV expression was significantly associated with clinical stage (P<0.01), histological grade (P<0.01), and clinical outcome (P<0.01). (PMID:12065094)
• sequestration of CaMKK may be the molecular mechanism by which catalytically inactive mutants of CaMKIV exert their “dominant-negative” functions within the cell (PMID:14701808)
• the Ca(2+)/CaM binding-autoinhibitory domain of CaMKIV is required for association of the kinase with PP2A (PMID:15143065)
• calcium/CaMKIV signaling pathway may play an important role in the excitation-mediated regulation of corticotropin releasing hormone synthesis (PMID:15591024)
• the function of CaMK II is essential for PAF-induced macrophage priming, while CaMK IV is not specific for priming by PAF and appears to have a direct link in TLR4-mediated events (PMID:15665723)
• CaMKIV is expressed in human sperm and may have a role in the regulation of human sperm motility (PMID:15840651)
• Results identify calcium/calmodulin-dependent kinase IV as being responsible for the increased expression of CREM and the decreased production of interleukin-2 in systemic lupus erythematosus T cells. (PMID:15841182)
• a novel link between TLR4 and a calcium-dependent signaling cascade comprising CaMKIV-CREB-Bcl-2 that is essential for DC survival. (PMID:17909078)
• Transgenic CaMKIV plays a modulatory role in the nucleus accumbens in anxiety-like behavior of adult CaMKIV variant mice. (PMID:18053176)
• CaMK-4 expression correlates positively with the ability to form long-term memory and implicates the decline of CaMKIV signaling mechanisms in age-related memory deficits. (PMID:18829949)
• CaMKIV plays a critical role in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription. (PMID:19001277)
• hnRNP L is an essential component of CaMKIV-regulated alternative splicing through CA repeats, with its phosphorylation likely playing a critical role. (PMID:19017650)
• a group of RNA elements are responsive to PKA and CaMKIV from in vivo selection (PMID:19386606)
• CaMKIV is a molecular link between Group I mGluRs and fragile X mental retardation protein in anterior cingulate cortex neurons (PMID:19436069)
• analysis of regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAc modification (PMID:19506079)
• these data indicate that the B subunits alpha and delta are essential for the interaction of PP2A with CaMKIV. (PMID:19538941)
• Data show that RA-induced repression of the CaMKIV signaling pathway may represent an early event in retinoid-dependent neuronal differentiation. (PMID:19633294)
• These findings suggest that PLC/CAMK IV-NF-kappaB is involved in RAGE mediated signaling pathway in human endothelial cells. (PMID:20171262)
• The regulation of RORalpha activity by PKA as well as CaMK-IV provides a new link in the signalling network that regulates metabolic processes such as glycogen and lipid metabolism. (PMID:21514275)
• Prolongevity genes are activated by CAMKIV, the levels of which are influenced by rs10491334, a single-nucleotide polymorphism associated with human longevity. (PMID:21612516)
• study suggests that the mutations in CAMK4 may lead to abnormal semen parameters (PMID:22897820)
• CaMK4 regulates beta-cell proliferation and apoptosis in a CREB-dependent manner and CaMK4-induced IRS-2 expression is important in these processes (PMID:23049845)
• Phosphorylated Notch1-IC by CaMKIV increases Notch1-IC stability, which enhances osteoclast differentiation. (PMID:23103515)
• An imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates risk for autism spectrum disorders. (PMID:24442360)
• CaMK4-dependent activation of AKT/mTOR and CREM-alpha underlies autoimmunity-associated Th17 imbalance. (PMID:24667640)
• Expression of CaMKIV inhibits autophosphorylation and activation of CaMKII, and elicits G0/G1cell cycle arrest,impairing cell proliferation. (PMID:25446257)
• The T-allele of rs10491334 in CAMK4 was associated with hypertension in the Uygur group. (PMID:26909912)
• Within the pH range 5.0-11.5, CAMK4 maintained both its secondary and tertiary structures, along with its function, whereas significant aggregation was observed at acidic pH (2.0-4.5). (PMID:27032767)
• hTau accumulation impairs synapse and memory by CaN-mediated suppression of nuclear CaMKIV/CREB signaling. (PMID:27298345)
• A positive association was not observed between rs10491334 in the CAMK4 gene and longevity in a Chinese population. (PMID:27659345)
• Genotype and allele frequencies of CAMKIV gene SNPs differed significantly between alcohol dependence patients and control subjects. The results of the present study suggest that CAMKIV might be a candidate alcohol dependence gene. (PMID:28734942)
• vanillin binds strongly to the active site cavity of CAMKIV and stabilized by a large number of non-covalent interactions. (PMID:28744811)
• CaMK4 is pivotal in immune and nonimmune podocyte injury and that its targeted cell-specific inhibition preserves podocyte structure and function and should have therapeutic value in lupus nephritis and podocytopathies, including focal segmental glomerulosclerosis. (PMID:29985166)
• Clinical disease severity directly correlates with calmodulin-dependent kinase IV (CaMKIV) activation, as does expression of proinflammatory cytokines and histologic features of colitis. In wild-type mice, CaMKIV activation is associated with increases in expression of 2 cell cycle proarrest signals: p53 and p21 (PMID:30113881)
• CaMK4 could be responsible for glycolysis, which contributes to the production of IL-17, and CaMK4 may contribute to aberrant expression of GLUT1 in T cells from patients with active SLE. (PMID:30462889)
• MiR-129-5p inhibits liver cancer growth by targeting calcium calmodulin-dependent protein kinase IV (CAMK4). (PMID:31624237)
• rs2300782 of gene CAMK4 is associated with diabetic retinopathy incidence and severity among Chinese Hui population. (PMID:31976761)
• Comparative transcriptome analysis reveals a potential role for CaMK4 in gammadeltaT17 cells from systemic lupus erythematosus patients with lupus nephritis. (PMID:31978801)
• CAMKK2-CAMK4 signaling regulates transferrin trafficking, turnover, and iron homeostasis. (PMID:32460794)
• MiR-507 inhibits the growth and invasion of trophoblasts by targeting CAMK4. (PMID:32572897)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	camk4	ENSDARG00000005372
mus_musculus	Camk4	ENSMUSG00000038128
rattus_norvegicus	Camk4	ENSRNOG00000020478

Paralogs (6): DCX (ENSG00000077279), MKNK1 (ENSG00000079277), MAPKAPK5 (ENSG00000089022), MKNK2 (ENSG00000099875), MAPKAPK3 (ENSG00000114738), MAPKAPK2 (ENSG00000162889)

Protein

Protein identifiers

Calcium/calmodulin-dependent protein kinase type IV — Q16566 (reviewed: Q16566)

Alternative names: CaM kinase-GR

All UniProt accessions (4): Q16566, D6RCD6, D6RE65, D6REY7

UniProt curated annotations — full annotation on UniProt →

Function. Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune response, inflammation, and memory consolidation. In the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes selection threshold during T-cell ontogeny. In CD4 memory T-cells, is required to link T-cell antigen receptor (TCR) signaling to the production of IL2, IFNG and IL4 (through the regulation of CREB and MEF2). Regulates the differentiation and survival phases of osteoclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphorylates the transcription activator CREB1 on ‘Ser-133’ in hippocampal neuron nuclei and contribute to memory consolidation and long term potentiation (LTP) in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1 and MAPK14/p38 and stimulate transcription through the phosphorylation of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A and STMN1/OP18.

Subunit / interactions. Monomer. Interacts with protein phosphatase 2A (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to Ca(2+)/calmodulin.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in brain, thymus, CD4 T-cells, testis and epithelial ovarian cancer tissue.

Post-translational modifications. Phosphorylated by CaMKK1 and CaMKK2 on Thr-200. Dephosphorylated by protein phosphatase 2A. Autophosphorylated on Ser-12 and Ser-13. Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.

Activity regulation. Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-200 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-200 results in a 10-20-fold increase in total activity to generate Ca(2+)/calmodulin-independent activity. Autophosphorylation of the N-terminus Ser-12 and Ser-13 is required for full activation. Inactivated by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-200, thereby terminating autonomous activity and helping to maintain the enzyme in its autoinhibited state.

Domain organisation. The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.

RefSeq proteins (5): NP_001310303, NP_001310304, NP_001310305, NP_001310306, NP_001735* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.17 — Ca2+/calmodulin-dependent protein kinase (BRENDA: 38 organisms, 300 substrates, 137 inhibitors, 35 Km, 17 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0071–178.29	13
BIOTINYLATED THR-ARG-SER-ALA-ILE-ARG-ARG-ALA-SER	0.0064–0.0158	4
GST-TAGGED GLUN2A	6.05–11.75	2
GST-TAGGED GLUN2B	0.35–5.93	2
MAP2	0.0007–0.0008	2
CALDESMON	0.0049	1
HISTONE IIIS	0.0445	1
LYS-LYS-ALA-LEU-ARG-ARG-GLN-GLU-ALA-VAL-ASP-ALA-	0.063	1
MICROTUBULE ASSOCIATED PROTEIN 2	0.0016	1
SYNTIDE-2	0.02	1
SYNTIDE-2 PEPTIDE	0.0221	1
MYELIN BASIC PROTEIN	—	0

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 (60 total): helix 13, mutagenesis site 8, strand 8, glycosylation site 7, modified residue 6, region of interest 5, sequence variant 4, turn 3, binding site 2, chain 1, domain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2W4O	X-RAY DIFFRACTION	2.17

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16566-F1	72.09	0.47

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): 164 (proton acceptor)

Ligand- & substrate-binding residues (2): 75; 52–60

Post-translational modifications (6): 12, 13, 200, 336, 341, 360

Glycosylation sites (7): 57, 58, 137, 189, 344, 345, 356

Mutagenesis-validated functional residues (8):

Position	Phenotype
12	loss of activity.
13	loss of activity.
57–58	loss of phosphorylation of creb1.
75	loss of activity; dominant negative form.
189	increases phosphorylation of creb1 2-fold. decreases total o-linked glycosylation 2-fold. increases atp-binding affinity
200	loss of activation by camkk1 or camkk2.
309–312	fully active ca2+/cam-independent kinase; when associated with 320-a-a-321.
320–321	fully active ca2+/cam-independent kinase; when associated with 309-a–a-312. loss of interaction with ppp2ca/ppp2cb.

Function

Pathways and Gene Ontology

Reactome pathways

34 pathways

ID	Pathway
R-HSA-111932	CaMK IV-mediated phosphorylation of CREB
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-442729	CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde
R-HSA-9022535	Loss of phosphorylation of MECP2 at T308
R-HSA-9022692	Regulation of MECP2 expression and activity
R-HSA-9617324	Negative regulation of NMDA receptor-mediated neuronal transmission
R-HSA-111885	Opioid Signalling
R-HSA-111933	Calmodulin induced events
R-HSA-111996	Ca-dependent events
R-HSA-111997	CaM pathway
R-HSA-112040	G-protein mediated events
R-HSA-112043	PLC beta mediated events
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1489509	DAG and IP3 signaling
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-212436	Generic Transcription Pathway
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-418594	G alpha (i) signalling events
R-HSA-438064	Post NMDA receptor activation events
R-HSA-442755	Activation of NMDA receptors and postsynaptic events
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8986944	Transcriptional Regulation by MECP2
R-HSA-9005891	Loss of function of MECP2 in Rett syndrome

MSigDB gene sets: 397 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_MEMORY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_DENDRITIC_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_COGNITION, GOBP_BEHAVIOR, MODULE_169, MORF_MSH3, REACTOME_CREB1_PHOSPHORYLATION_THROUGH_THE_ACTIVATION_OF_CAMKII_CAMKK_CAMKIV_CASCASDE, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, MODULE_64, MORF_BRCA1, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN

GO Biological Process (11): adaptive immune response (GO:0002250), protein phosphorylation (GO:0006468), inflammatory response (GO:0006954), signal transduction (GO:0007165), long-term memory (GO:0007616), regulation of T cell differentiation in thymus (GO:0033081), intracellular signal transduction (GO:0035556), myeloid dendritic cell differentiation (GO:0043011), regulation of osteoclast differentiation (GO:0045670), positive regulation of DNA-templated transcription (GO:0045893), immune system process (GO:0002376)

GO Molecular Function (10): calcium/calmodulin-dependent protein kinase activity (GO:0004683), calmodulin binding (GO:0005516), ATP binding (GO:0005524), calcium-dependent protein serine/threonine kinase activity (GO:0009931), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Calmodulin induced events	1
Mitochondrial biogenesis	1
Post NMDA receptor activation events	1
Loss of function of MECP2 in Rett syndrome	1
Transcriptional Regulation by MECP2	1
Activation of NMDA receptors and postsynaptic events	1
G alpha (i) signalling events	1
CaM pathway	1
PLC beta mediated events	1
Ca-dependent events	1
DAG and IP3 signaling	1
Opioid Signalling	1
G-protein mediated events	1
Transmission across Chemical Synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
protein serine/threonine kinase activity	2
protein kinase activity	2
intracellular membrane-bounded organelle	2
immune response	1
phosphorylation	1
protein modification process	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
memory	1
T cell differentiation in thymus	1
regulation of T cell differentiation	1
signal transduction	1
myeloid dendritic cell activation	1
myeloid leukocyte differentiation	1
dendritic cell differentiation	1
regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
biological_process	1
protein binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate 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
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
nucleolus	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

3038 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAMK4	CALML3	P27482	987
CAMK4	CALML5	Q9NZT1	987
CAMK4	CALML6	Q8TD86	986
CAMK4	CALML4	Q96GE6	986
CAMK4	CALM1	P02593	972
CAMK4	CREB1	P16220	870
CAMK4	CYP11B2	P19099	611
CAMK4	DCX	O43602	596
CAMK4	SYN1	P17600	589
CAMK4	BDNF	P23560	581
CAMK4	GLIS1	Q8NBF1	545
CAMK4	PRM2	P04554	541
CAMK4	TNP2	Q05952	532
CAMK4	AGT	P01019	522
CAMK4	MEF2D	Q14814	517

IntAct

23 interactions, top by confidence:

A	B	Type	Score
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
CALM1	CAMK4	psi-mi:“MI:0407”(direct interaction)	0.440
HSP90AB1	CAMK4	psi-mi:“MI:0915”(physical association)	0.400
CAMK4	ANKRD28	psi-mi:“MI:0914”(association)	0.350
RIPK2	CNOT1	psi-mi:“MI:0914”(association)	0.350
FRK	CNOT1	psi-mi:“MI:0914”(association)	0.350
CAMK4	CNOT1	psi-mi:“MI:0914”(association)	0.350
AAK1	PDHX	psi-mi:“MI:0914”(association)	0.350
CAMKK1	CTSA	psi-mi:“MI:0914”(association)	0.350
GYPA	HYKK	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
CCT8L2	DVL2	psi-mi:“MI:0914”(association)	0.350
LGI1	APAF1	psi-mi:“MI:0914”(association)	0.350
TRIM17	MTMR1	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350
LY86	MAP2K7	psi-mi:“MI:0914”(association)	0.350
PPT1	CLGN	psi-mi:“MI:0914”(association)	0.350

BioGRID (66): GIT1 (Affinity Capture-MS), ARHGEF7 (Affinity Capture-MS), GIT2 (Affinity Capture-MS), ANKRD28 (Affinity Capture-MS), PPP6R2 (Affinity Capture-MS), ANKRD52 (Affinity Capture-MS), CAMK4 (Affinity Capture-MS), CAMK4 (Affinity Capture-MS), CAMK4 (Affinity Capture-MS), CAMK4 (Proximity Label-MS), CAMK4 (Affinity Capture-MS), CAMK4 (Affinity Capture-MS), CAMK4 (Affinity Capture-MS), GIT1 (Affinity Capture-MS), GIT2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3S724, A4IGM9, A4IIW7, A5GFW1, B0VXL7, B6A7Q3, C0RW22, D7UQM5, F4I4F2, O08605, O14965, O35495, O55099, O59790, O70126, O80673, O94921, P18266, P27466, P49841, P59241, P97477, Q00771, Q0VD22, Q13555, Q16566, Q2TA06, Q501Q9, Q58D94, Q5XIT0, Q66JF3, Q6BVA0, Q6C3J2, Q6CWQ4, Q6DE08, Q6DGS3, Q6GPL3, Q6Z8C8, Q755C4, Q7YRC6

Diamond homologs: A0A2I0BVG8, A0A509AFG4, A0A509AHB6, A0A509ALV6, A0A509AQE6, A0A5K1K8H0, A2XFF4, A8X6H4, B8BBT7, E9PT87, F4JBP3, O15865, O22932, O61267, O70150, O80673, P05986, P08414, P13234, P18654, P22216, P22517, P25323, P27466, P28582, P34101, P40376, P51812, P53681, P53684, P62343, P62344, P62345, P92958, P93759, Q00771, Q09170, Q0D715, Q0VD22, Q10KY3

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
CAMK4	“up-regulates activity”	CREB1	phosphorylation
CAMKK1	up-regulates	CAMK4	phosphorylation
CAMK4	up-regulates	CREB1	phosphorylation
CAMK4	down-regulates	PHB2	phosphorylation
CAMK4	up-regulates	HNRNPL	phosphorylation
CAMK4	down-regulates	HDAC5	phosphorylation
CAMK4	unknown	NOVA2	phosphorylation
CAMK4	“up-regulates quantity”	NOVA2	phosphorylation
PPM1F	“down-regulates activity”	CAMK4	dephosphorylation
CAMK4	“up-regulates activity”	HMGB1	phosphorylation
CAMK4	“down-regulates activity”	GSK3B	phosphorylation
CAMK4	“up-regulates quantity by stabilization”	NOTCH1	phosphorylation
CAMK4	“up-regulates activity”	LIMK1	phosphorylation
CAMK4	down-regulates	STMN1	phosphorylation
CAMK4	down-regulates	HDAC4	phosphorylation
CAMK4	“up-regulates activity”	CREBBP	phosphorylation
CAMK4	“down-regulates activity”	HDAC4	phosphorylation
CAMK4	“down-regulates activity”	NOS1	phosphorylation
CAMKK2	“up-regulates activity”	CAMK4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	92
Likely benign	6
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2507053	NM_001744.6(CAMK4):c.929T>C (p.Met310Thr)	Pathogenic
560302	NM_001744.6(CAMK4):c.981+1G>A	Pathogenic

SpliceAI

2306 predictions. Top by Δscore:

Variant	Effect	Δscore
5:111344021:AAG:A	acceptor_gain	1.0000
5:111344021:AAGG:A	acceptor_gain	1.0000
5:111376854:CCCTA:C	acceptor_loss	1.0000
5:111376855:CCTAG:C	acceptor_loss	1.0000
5:111376857:TA:T	acceptor_loss	1.0000
5:111376858:A:AG	acceptor_gain	1.0000
5:111376858:A:AT	acceptor_loss	1.0000
5:111376859:G:GA	acceptor_loss	1.0000
5:111376859:G:GG	acceptor_gain	1.0000
5:111376859:GATAA:G	acceptor_gain	1.0000
5:111394706:CCA:C	acceptor_loss	1.0000
5:111394708:AG:A	acceptor_gain	1.0000
5:111394708:AGGA:A	acceptor_loss	1.0000
5:111394709:GG:G	acceptor_gain	1.0000
5:111394709:GGATT:G	acceptor_gain	1.0000
5:111394778:TTGCT:T	donor_gain	1.0000
5:111394780:GCT:G	donor_gain	1.0000
5:111394781:CT:C	donor_gain	1.0000
5:111394781:CTGTA:C	donor_loss	1.0000
5:111394782:TGTA:T	donor_loss	1.0000
5:111394783:G:GG	donor_gain	1.0000
5:111394783:GTA:G	donor_loss	1.0000
5:111394784:T:A	donor_loss	1.0000
5:111394785:A:AG	donor_loss	1.0000
5:111394786:AGTA:A	donor_loss	1.0000
5:111394787:G:C	donor_loss	1.0000
5:111394787:G:GG	donor_gain	1.0000
5:111446684:A:AG	acceptor_gain	1.0000
5:111446684:AGT:A	acceptor_loss	1.0000
5:111446685:G:GA	acceptor_gain	1.0000

AlphaMissense

3089 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:111224640:G:A	G53R	1.000
5:111224640:G:C	G53R	1.000
5:111224641:G:A	G53E	1.000
5:111344025:G:A	G55S	1.000
5:111344025:G:C	G55R	1.000
5:111344025:G:T	G55C	1.000
5:111344026:G:A	G55D	1.000
5:111344026:G:T	G55V	1.000
5:111344034:T:C	S58P	1.000
5:111344035:C:T	S58F	1.000
5:111344041:T:A	V60E	1.000
5:111344051:C:G	C63W	1.000
5:111344080:C:A	A73D	1.000
5:111344085:A:C	K75Q	1.000
5:111344085:A:G	K75E	1.000
5:111344086:A:T	K75I	1.000
5:111344087:A:C	K75N	1.000
5:111344087:A:T	K75N	1.000
5:111344092:T:C	L77S	1.000
5:111374874:G:A	E89K	1.000
5:111374875:A:C	E89A	1.000
5:111374875:A:G	E89G	1.000
5:111374875:A:T	E89V	1.000
5:111374876:G:C	E89D	1.000
5:111374876:G:T	E89D	1.000
5:111374887:T:C	L93P	1.000
5:111376861:T:A	I102K	1.000
5:111376903:T:C	L116P	1.000
5:111376906:T:A	V117D	1.000
5:111376909:T:C	L118P	1.000

dbSNP variants (sampled 300 via entrez): RS1000016744 (5:111325312 C>T), RS1000031602 (5:111478621 A>C,G), RS1000050513 (5:111244081 T>G), RS1000051957 (5:111389049 A>T), RS1000069608 (5:111401656 C>T), RS1000076164 (5:111487181 A>G), RS1000077875 (5:111287415 A>C), RS1000084723 (5:111291688 T>C), RS1000089961 (5:111325488 A>C), RS1000121886 (5:111362429 A>G), RS1000132264 (5:111494997 T>A,G), RS1000133383 (5:111247629 T>C), RS1000152237 (5:111412707 T>C), RS1000161058 (5:111491041 C>G,T), RS1000172784 (5:111464152 C>T)

Disease associations

OMIM: gene MIM:114080 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (3): severe combined immunodeficiency (MONDO:0015974), intellectual disability (MONDO:0001071), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Severe combined immunodeficiency (Orphanet:183660), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

HPO	Term
HP:0004430	Severe combined immunodeficiency

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST000094_7	Blood pressure	4.000000e-06
GCST001081_1	Longevity	2.000000e-06
GCST001915_10	Alzheimer’s disease (cognitive decline)	2.000000e-06
GCST002083_18	Self-reported allergy	2.000000e-20
GCST002084_11	Allergic sensitization	5.000000e-14
GCST002136_18	Periodontitis (PAL4Q3)	8.000000e-07
GCST003990_2	Allergy	3.000000e-17
GCST005038_18	Allergic disease (asthma, hay fever or eczema)	5.000000e-46
GCST006409_36	Allergic rhinitis	3.000000e-26
GCST007563_10	Allergic disease (asthma, hay fever or eczema)	5.000000e-20
GCST007797_27	Asthma onset (childhood vs adult)	2.000000e-10
GCST007798_74	Asthma	6.000000e-37
GCST007800_33	Asthma (childhood onset)	4.000000e-66
GCST007932_97	Medication use (thyroid preparations)	7.000000e-09
GCST008916_116	Asthma	4.000000e-20
GCST008916_14	Asthma	4.000000e-10
GCST008916_62	Asthma	3.000000e-08
GCST009798_4	Asthma	1.000000e-14
GCST009798_60	Asthma	1.000000e-44
GCST009798_71	Asthma	2.000000e-18
GCST010571_28	Autoimmune thyroid disease	3.000000e-11
GCST010984_16	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	9.000000e-12
GCST010985_51	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	5.000000e-12
GCST012137_2	Motor coordination	8.000000e-06
GCST90002388_318	Lymphocyte count	4.000000e-17
GCST90002389_209	Lymphocyte percentage of white cells	5.000000e-14
GCST90014023_20	Type 1 diabetes	5.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0005298	allergic sensitization measurement
EFO:0004847	age at onset
EFO:0009933	Thyroid preparation use measurement
EFO:0010749	motor function measurement
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016511	Severe Combined Immunodeficiency	C16.320.798.750; C16.614.815; C18.452.284.800; C20.673.795.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2494 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

14 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 154,903 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL3545307	MERESTINIB	2	851
CHEMBL2140408	AMG-900	1	675
CHEMBL3128043	PF-03758309	1	233
CHEMBL494089	GSK-690693	1	2,061
CHEMBL574738	AST-487	1	451

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs306104	CAMK4		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CAMK1 family

Binding affinities (BindingDB)

12 measured of 12 human assays (12 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
8-((6-Chloropyrimidin-4-yl)oxy)quinoline (Compound 1)	KI	0.0109 nM
Staurosporine	KD	1.7 nM
7-((6-((5-Methoxy-1H-benzo[d]imidazol-2-yl)thio)pyrimidin-4-yl)oxy)-4-methyl-2H-chromen-2-one (Molecule 5)	KI	1350 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
4-Methyl-7-((6-(quinolin-8-yloxy)pyrimidin-4-yl)oxy)-2H-chromen-2one (Molecule 4)	KI	1450 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
7-[(6-Chloropyrimidin-4-yl)oxy]-4-methyl-2H-chromen-2-one (Compound 2)	KI	3570 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM
6-((5-Methoxy-1H-benzo[d]imidazol-2-yl)thio)-N-(4-methoxyphenyl)pyrimidin-4-amine (Molecule 3)	KI	10100 nM
8-((6-((5-Methoxy-1H-benzo[d]imidazol-2-yl)thio)pyrimidin-4-yl)oxy)quinoline (Molecule 2)	KI	24400 nM
8-((6-(Naphthalen-2-yloxy)pyrimidin-4-yl)oxy)quinoline (Molecule 1)	KI	667000 nM

ChEMBL bioactivities

42 potent at pChembl≥5 of 46 total, top 35 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.54	IC50	28.9	nM	STAUROSPORINE
7.52	Kd	30	nM	TAE-684
7.39	Kd	41	nM	STAUROSPORINE
6.96	IC50	109	nM	STAUROSPORINE
6.86	IC50	138	nM	STAUROSPORINE
6.80	IC50	157	nM	STAUROSPORINE
6.71	Kd	196	nM	RUXOLITINIB
6.44	Kd	360	nM	CHEMBL2048872
6.43	Kd	370	nM	GSK-690693
6.39	Kd	408	nM	PF-03758309
6.38	Kd	421	nM	GILTERITINIB
6.33	Kd	470	nM	CHEMBL464552
6.20	Kd	635	nM	CERITINIB
6.15	Kd	710	nM	CHEMBL379218
6.05	Kd	890	nM	SUNITINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.74	Kd	1817	nM	AMG-900
5.64	Kd	2274	nM	DABRAFENIB
5.63	Kd	2343	nM	CHEMBL3752910
5.63	ED50	2343	nM	CHEMBL3752910
5.57	Kd	2700	nM	SU-014813
5.56	Kd	2777	nM	CHEMBL5653589
5.56	ED50	2777	nM	CHEMBL5653589
5.53	Kd	2970	nM	SUNITINIB
5.52	IC50	3000	nM	CHEMBL4795714
5.52	Kd	3000	nM	LESTAURTINIB
5.50	Kd	3200	nM	ALVOCIDIB
5.49	Kd	3256	nM	MERESTINIB
5.43	Kd	3700	nM	AST-487
5.43	Kd	3700	nM	NINTEDANIB
5.26	Kd	5460	nM	ALVOCIDIB
5.22	Kd	5955	nM	CHEMBL3991933
5.00	IC50	1e+04	nM	CHEMBL3884319

PubChem BioAssay actives

40 with measured affinity, of 1255 total; 27 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
8-(6-chloropyrimidin-4-yl)oxyquinoline	1802648: Molecular Docking from Article 10.1111/cbdd.12898: “Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV.”	ki	<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	2195242: Inhibition of CAMK4 (unknown origin) incubated for 120 mins in presence of 33P-ATP by radiometric kinase assay	ic50	0.0289	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624843: Binding constant for CAMK4 kinase domain	kd	0.0300	uM
Ruxolitinib	1424930: 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	0.1960	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	624843: Binding constant for CAMK4 kinase domain	kd	0.3700	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	1424930: 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	0.4080	uM
Gilteritinib	1424930: 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	0.4210	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	624843: Binding constant for CAMK4 kinase domain	kd	0.4700	uM
Ceritinib	1424930: 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	0.6350	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	624843: Binding constant for CAMK4 kinase domain	kd	0.7100	uM
Sunitinib	435152: Binding constant for CAMK4 kinase domain	kd	0.8900	uM
7-[6-[(6-methoxy-1H-benzimidazol-2-yl)sulfanyl]pyrimidin-4-yl]oxy-4-methylchromen-2-one	1802648: Molecular Docking from Article 10.1111/cbdd.12898: “Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV.”	ki	1.3514	uM
4-methyl-7-(6-quinolin-8-yloxypyrimidin-4-yl)oxychromen-2-one	1802648: Molecular Docking from Article 10.1111/cbdd.12898: “Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV.”	ki	1.4493	uM
N-[4-[[3-(2-aminopyrimidin-4-yl)-2-pyridinyl]oxy]phenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine	1424930: 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	1.8170	uM
Dabrafenib	1424930: 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	2.2740	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147986: Binding affinity to human CAMK4 incubated for 45 mins by Kinobead based pull down assay	kd	2.3432	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435152: Binding constant for CAMK4 kinase domain	kd	2.7000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147986: Binding affinity to human CAMK4 incubated for 45 mins by Kinobead based pull down assay	kd	2.7768	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	507859: Binding affinity to CAMK4	kd	3.0000	uM
1-pentyl-4-(2-phenylmethoxyphenyl)imidazol-2-amine;hydrochloride	1734152: Inhibition of wild-type human CAMK4 using KKLNRTLSFAEPG peptide as substrate in presence of Ca2+ calmodulin and [gamma-33P]-ATP by radiometric hotspot kinase assay	ic50	3.0000	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	435152: Binding constant for CAMK4 kinase domain	kd	3.2000	uM
N-[3-fluoro-4-[1-methyl-6-(1H-pyrazol-4-yl)indazol-5-yl]oxyphenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide	1424930: 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	3.2560	uM
7-(6-chloropyrimidin-4-yl)oxy-4-methylchromen-2-one	1802648: Molecular Docking from Article 10.1111/cbdd.12898: “Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV.”	ki	3.5714	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435152: Binding constant for CAMK4 kinase domain	kd	3.7000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624843: Binding constant for CAMK4 kinase domain	kd	3.7000	uM
3-(2-methyl-1,3-benzoxazol-5-yl)-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-4-amine	1424930: 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	5.9550	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1336062: Inhibition of human recombinant full length GST-tagged CAMK4 expressed in Escherichia coli	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	4
trichostatin A	increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases methylation, increases expression	3
bisphenol A	increases expression, increases methylation	2
Estradiol	decreases reaction, increases activity, affects cotreatment, increases expression	2
Nickel	increases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	decreases expression, increases abundance, affects cotreatment	1
methylselenic acid	increases expression	1
beta-lapachone	decreases expression	1
arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	1
casticin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2’,3’,4’,5’-tetrachloro-4-biphenylol	decreases reaction, increases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dimethylarsinous acid	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	affects expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	decreases expression, increases abundance, affects cotreatment	1
Cocaine	increases response to substance	1

ChEMBL screening assays

342 unique, capped per target: 342 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1012674	Binding	Inhibition of CAMK4 at 5 uM	Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases. — J Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1LU	Abcam K-562 CAMK4 KO	Cancer cell line	Female
CVCL_D2IF	Abcam Raji CAMK4 KO	Cancer cell line	Male
CVCL_D8ID	Ubigene HCT 116 CAMK4 KO	Cancer cell line	Male
CVCL_D9AX	Ubigene HEK293 CAMK4 KO	Transformed cell line	Female
CVCL_D9ZA	Ubigene HeLa CAMK4 KO	Cancer cell line	Female
CVCL_UQ26	Abcam Jurkat CAMK4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT01420627	PHASE3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00794508	PHASE2	COMPLETED	MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
NCT01182675	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02177760	PHASE2	WITHDRAWN	Sirolimus Prophylaxis for aGVHD in TME SCID
NCT03619551	PHASE2	ACTIVE_NOT_RECRUITING	Conditioning SCID Infants Diagnosed Early
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00008450	PHASE1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT00028236	PHASE1	COMPLETED	Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)
NCT00152100	PHASE1	COMPLETED	Transplantation of Hematopoietic Cells in Children With Severe Combined Immunodeficiency Syndrome
NCT02860559	PHASE1	UNKNOWN	Safety and Early Efficacy Study of TBX-1400 in Patients With Severe Combined Immunodeficiency
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
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
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00228852	PHASE1/PHASE2	COMPLETED	IMM 0212: Busulfan With Fludarabine and Antithymocyte Globulin as Preparative Therapy for Hematopoietic Stem Cell Transplant for the Treatment of Severe Congenital T-Cell Immunodeficiency
NCT00579137	PHASE1/PHASE2	TERMINATED	Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders
NCT01129544	PHASE1/PHASE2	COMPLETED	Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT02127892	PHASE1/PHASE2	TERMINATED	SCID Bu/Flu/ATG Study With T Cell Depletion
NCT02963064	PHASE1/PHASE2	TERMINATED	JSP191 Antibody Targeting Conditioning in SCID Patients
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT03538899	PHASE1/PHASE2	RECRUITING	Autologous Gene Therapy for Artemis-Deficient SCID
NCT03597594	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Haplocompatible Transplant Using TCRα/β Depletion Followed by CD45RA-Depleted Donor Lymphocyte Infusions for Severe Combined Immunodeficiency (SCID)