CAMKK2

Summary

CAMKK2 (calcium/calmodulin dependent protein kinase kinase 2, HGNC:1470) is a protein-coding gene on chromosome 12q24.31, encoding Calcium/calmodulin-dependent protein kinase kinase 2 (Q96RR4). Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes.

The product of this gene belongs to the Serine/Threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. The major isoform of this gene plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4. Protein products of this gene also phosphorylate AMP-activated protein kinase (AMPK). This gene has its strongest expression in the brain and influences signalling cascades involved with learning and memory, neuronal differentiation and migration, neurite outgrowth, and synapse formation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. The identified isoforms differ in their ability to undergo autophosphorylation and to phosphorylate downstream kinases.

Source: NCBI Gene 10645 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 101 total
• Druggable target: yes — 42 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001270485

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1470
Approved symbol	CAMKK2
Name	calcium/calmodulin dependent protein kinase kinase 2
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	CAMKK, KIAA0787, CAMKKB, MGC15254
Ensembl gene	ENSG00000110931
Ensembl biotype	protein_coding
OMIM	615002
Entrez	10645

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 26 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000324774, ENST00000337174, ENST00000347034, ENST00000392473, ENST00000392474, ENST00000402834, ENST00000404169, ENST00000412367, ENST00000446440, ENST00000535524, ENST00000538733, ENST00000539380, ENST00000542540, ENST00000543477, ENST00000544485, ENST00000545538, ENST00000652382, ENST00000907127, ENST00000907128, ENST00000907129, ENST00000907130, ENST00000907131, ENST00000907132, ENST00000943500, ENST00000943501, ENST00000943502, ENST00000943503, ENST00000943504, ENST00000943505

RefSeq mRNA: 9 — MANE Select: NM_001270485 NM_001270485, NM_001270486, NM_006549, NM_153499, NM_153500, NM_172214, NM_172215, NM_172216, NM_172226

CCDS: CCDS44999, CCDS53837, CCDS58283, CCDS9216, CCDS9217, CCDS9218, CCDS9219

Canonical transcript exons

ENST00000404169 — 17 exons

Exon	Start	End
ENSE00001111875	121260319	121260355
ENSE00001286308	121255783	121255804
ENSE00001286319	121263806	121263939
ENSE00001805123	121274056	121274585
ENSE00002220582	121296638	121296709
ENSE00003466177	121237692	121240869
ENSE00003468232	121255550	121255638
ENSE00003482628	121253273	121253472
ENSE00003512507	121249787	121249874
ENSE00003563412	121248606	121248734
ENSE00003568718	121249961	121250034
ENSE00003593976	121269528	121269581
ENSE00003602180	121270898	121270945
ENSE00003610777	121244573	121244615
ENSE00003656314	121268638	121268689
ENSE00003657710	121245140	121245240
ENSE00003678606	121252661	121252714

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2991 / max 460.1201, expressed in 1809 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133719	17.5272	1809
133720	0.3920	194
206934	0.1568	68
206935	0.0677	18
133708	0.0665	10
133710	0.0436	9
133709	0.0263	7
133711	0.0191	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar cortex	UBERON:0002129	99.37	gold quality
cerebellar hemisphere	UBERON:0002245	99.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.37	gold quality
cerebellum	UBERON:0002037	99.34	gold quality
cerebellar vermis	UBERON:0004720	99.26	gold quality
paraflocculus	UBERON:0005351	98.56	gold quality
right frontal lobe	UBERON:0002810	97.49	gold quality
prefrontal cortex	UBERON:0000451	97.23	gold quality
frontal cortex	UBERON:0001870	97.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.94	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.92	gold quality
orbitofrontal cortex	UBERON:0004167	96.82	gold quality
pons	UBERON:0000988	96.74	gold quality
pancreatic ductal cell	CL:0002079	96.62	silver quality
superior frontal gyrus	UBERON:0002661	96.59	gold quality
neocortex	UBERON:0001950	96.53	gold quality
adult organism	UBERON:0007023	96.40	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.24	gold quality
occipital lobe	UBERON:0002021	95.93	gold quality
cortical plate	UBERON:0005343	95.93	gold quality
parietal lobe	UBERON:0001872	95.84	gold quality
middle temporal gyrus	UBERON:0002771	95.72	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.65	gold quality
cingulate cortex	UBERON:0003027	95.49	gold quality
anterior cingulate cortex	UBERON:0009835	95.44	gold quality
primary visual cortex	UBERON:0002436	95.41	gold quality
postcentral gyrus	UBERON:0002581	95.37	gold quality
frontal pole	UBERON:0002795	95.32	gold quality
cerebral cortex	UBERON:0000956	95.22	gold quality
parietal pleura	UBERON:0002400	94.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, CEBPD

miRNA regulators (miRDB)

142 targeting CAMKK2, 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-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-4283	100.00	66.42	2097
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6768-5P	99.92	67.36	1942

Literature-anchored findings (GeneRIF, showing 40)

• There is a significant basal activity and phosphorylation of AMPK in LKB1-deficient cells that can be stimulated by Ca2+ ionophores, and studies using the CaMKK inhibitor STO-609 and isoform-specific siRNAs show that CaMKKbeta is required for this effect (PMID:16054095)
• Overexpression of CaMKKbeta in mammalian cells increases AMPK activity, whereas pharmacological inhibition of CaMKK, or downregulation of CaMKKbeta using RNA interference, almost completely abolishes AMPK activation (PMID:16054096)
• Endothelial cells possess two pathways to activate AMPK, one Ca2+/CaMKKbeta dependent and one AMP/LKB1 dependent. (PMID:16880506)
• a prominent association found between severity of panic- and agoraphobia symptoms and an exonic SNP (rs3817190) in the CaMKKb gene and a trend for association with an exonic SNP in P2RX7 (rs1718119) with severity scores in the panic- and agoraphobia scale (PMID:17197037)
• modulating basal AMPK and CAMKKB activity in the hypothalamus is essential for maintaining tight regulation of pathways contributing to food intake (PMID:18436530)
• Growth of cervical cancer cells was inhibited through activation of CAMKK2 and LBK1. (PMID:19407487)
• Data show that that the prototypical CaM target sequence skMLCK, a fragment from skeletal muscle myosin light chain kinase, binds to CaM in a highly cooperative way, while only a lower degree of interdomain binding cooperativity emerges for CaMKK. (PMID:19667195)
• ERK activation and cell growth require CaM kinases in MCF-7 breast cancer cells (PMID:19763792)
• Calmodulin-dependent protein kinase kinase-beta activates AMPK without forming a stable complex. There is a synergistic effects of Ca2+ and AMP. (PMID:19958286)
• CaMKK is involved in both S1P receptor- and SR-BI-mediated phosphorylation of AMPK, Akt, and eNOS. (PMID:20018878)
• These results suggest that CaMKK is an important factor for human cytomegalovirus replication and human cytomegalovirus-mediated glycolytic activation. (PMID:21084482)
• phosphorylation of CaMKKbeta regulates its half-life. (PMID:21669867)
• Findings reveal that hypoxia can trigger AMPK activation in the apparent absence of increased [AMP] through ROS-dependent CRAC channel activation, leading to increases in cytosolic calcium that activate the AMPK upstream kinase CaMKKbeta. (PMID:21670147)
• Our results demonstrate that CaMKKbeta and AMP-activated protein kinase form a unique signaling complex (PMID:21807092)
• Data show that protein kinase A (PKA) regulates the alternative splicing of Ca(2)/calmodulin-dependent protein kinase kinase 2 (CaMKK2) to produce variants that differentially modulate neuronal differentiation. (PMID:21957496)
• Results suggest that in PCa progression, CaMKK2 and the AR are in a feedback loop in which CaMKK2 is induced by the AR to maintain AR activity, AR-dependent cell cycle control, and continued cell proliferation. (PMID:22654108)
• Calcium/calmodulin-dependent protein kinase kinase 2 has roles in signaling and pathophysiology [review] (PMID:22778263)
• amino acid starvation regulates autophagy in part through an increase in cellular Ca(2+) that activates a CaMKK-beta-AMPK pathway and inhibits mTORC1, which results in ULK1 stimulation (PMID:23027865)
• CaMKKbeta is involved in AMP-activated protein kinase activation by baicalin in LKB1 deficient cell lines. (PMID:23110126)
• CaMKIIalpha phosphorylation was enhanced by S-Allyl cysteine treatment in a concentration- and time-dependent manner, which paralleled AMPK activation. (PMID:23465592)
• Pulsatile shear stress mimicking atheroprotective flow increases the level of sirtuin (SIRT)1 in cultured endothelial cells by enhancing its stability, an effect abolished by inhibition or knockdown of CaMKKbeta. (PMID:23754392)
• evidence supports that CAMKK2 is a novel schizophrenia susceptibility gene. (PMID:23958956)
• PCa patients with miR-224-low/CAMKK2-high expression more frequently had shorter overall survival. (PMID:25394900)
• CaMKKbeta-AMPKalpha2 signaling contributes to mitotic Golgi fragmentation and the G2/M transition in mammalian cells. (PMID:25590814)
• CaMKK2 plays a pivotal role in the calcium signaling cascade regulating adrenal aldosterone production. (PMID:25679868)
• Silencing of CAMKK2 using siRNA significantly reduced cell proliferation, colony formation and invasion of gastric cancer cells. (PMID:25756516)
• CAMKK2 protein is highly up regulated in hepatocellular carcinoma. (PMID:25847065)
• For the first time, we showed that rs1063843, a single nucleotide polymorphism located in the CAMKK2 gene, is highly associated with bipolar disorder (PMID:26354101)
• CaMKK2 (and Nup62) are required for optimal androgen receptor transcriptional activity in castrate resistant prostate cancer cells. (PMID:26552607)
• CAMKK2 exhibited the strongest associations with HIV-associated sensory neuropathy (HIV-SN), with two SNPs and six haplotypes predicting SN status in black Southern Africans. (PMID:26785644)
• Clopidogrel diminishes TNFalpha-stimulated VCAM-1 expression at least in part via HO-1 induction and CaMKKbeta/AMPK/Nrf2 pathway in endothelial cells. (PMID:26824050)
• Study used three cognitive tasks and fMRI to provide convergent evidence of a link between the rs1063843 SNP of CAMKK2 and the function of the dorsolateral prefrontal cortex. In addition, this polymorphism was associated with the function of the striatum during a working memory task. (PMID:27004598)
• This study showed that the expression level of CAMKK2 could be regulated by promoter methylation. CAMKK2 serves as a prognostic marker in gliomas and could be a potential therapeutic target in gliomas. (PMID:27012733)
• Site-directed mutagenesis analysis revealed that Leu(358) in CaMKKbeta/Ile(322) in CaMKKalpha confer, at least in part, a distinct recognition of AMPK but not of CaMKIalpha. (PMID:27151216)
• This study provides insight into functionally disruptive, rare-variant mutations in human CaMKK2, which have the potential to influence risk and burden of disease associated with aberrant CaMKK2 activity in human populations carrying these variants. (PMID:28230171)
• Single nucleotide polymorphism in CAMKK2 gene is associated with pulmonary non-tuberculous mycobacterial disease. (PMID:28233049)
• Silencing of TRPC5 and inhibition of autophagy reverses adriamycin drug resistance in breast carcinoma via CaMKKbeta/AMPKalpha/mTOR pathway. (PMID:28600513)
• Data suggest that CAMKK2 is highly expressed in high-grade ovarian cancer and ovarian cancer cell lines; CAMKK2 directly activates Akt1 by phosphorylation at Thr-308 in a Ca2+/calmodulin-dependent manner; CAMKK2 knockdown or inhibition decreases Akt1 phosphorylation at Thr-308 and Ser-473. (CAMKK2 = calcium/calmodulin dependent protein kinase kinase 2; AKT1 = AKT serine/threonine kinase 1) (PMID:28634229)
• Three single nucleotide polymorphisms (SNPs) within P2X4R and two SNPs within CAMKK2 influenced concentrations of TNFalpha in peripheral blood mononuclear cells, but these SNP did not associate with risk for HIV-associated sensory neuropathy in South Africans. (PMID:29428485)
• 14-3-3gamma protein directly interacts with the kinase domain of CaMKK2 and the region containing the inhibitory phosphorylation site Thr(145) within the N-terminal extension. CaMKK isoforms differ in their 14-3-3-mediated regulations and the interaction between 14-3-3 protein and the N-terminal 14-3-3-binding motif of CaMKK2 might be stabilized by small-molecule compounds. (PMID:29649512)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Camkk2	ENSMUSG00000029471
rattus_norvegicus	Camkk2	ENSRNOG00000001309

Paralogs (22): CAMKK1 (ENSG00000004660), CAMK1G (ENSG00000008118), CAMK2B (ENSG00000058404), CAMK2A (ENSG00000070808), MYLK2 (ENSG00000101306), STK11 (ENSG00000118046), STK33 (ENSG00000130413), PNCK (ENSG00000130822), DCLK1 (ENSG00000133083), CAMK1 (ENSG00000134072), MYLK3 (ENSG00000140795), CAMK2D (ENSG00000145349), MYLK4 (ENSG00000145949), PSKH2 (ENSG00000147613), CAMK2G (ENSG00000148660), PHKG2 (ENSG00000156873), PSKH1 (ENSG00000159792), DCLK3 (ENSG00000163673), CAMKV (ENSG00000164076), PHKG1 (ENSG00000164776), DCLK2 (ENSG00000170390), CAMK1D (ENSG00000183049)

Protein

Protein identifiers

Calcium/calmodulin-dependent protein kinase kinase 2 — Q96RR4 (reviewed: Q96RR4)

Alternative names: Calcium/calmodulin-dependent protein kinase kinase beta

All UniProt accessions (4): Q96RR4, F5GZ00, F5H360, F5H4I7

UniProt curated annotations — full annotation on UniProt →

Function. Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin-binding domain are inactive. Efficiently phosphorylates 5’-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals. Seems to be involved in hippocampal activation of CREB1. May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching.

Subunit / interactions. Interacts with calmodulin.

Subcellular location. Nucleus. Cytoplasm. Cell projection. Neuron projection.

Tissue specificity. Ubiquitously expressed with higher levels in the brain. Intermediate levels are detected in spleen, prostate, thyroid and leukocytes. The lowest level is in lung.

Post-translational modifications. Autophosphorylated and phosphorylated by PKA. Each isoform may show a different pattern of phosphorylation.

Activity regulation. Activated by Ca(2+)/calmodulin. Binding of calmodulin may relieve intrasteric autoinhibition. Autophosphorylation does not alter activity or regulation by Ca(2+)/calmodulin. In part, activity is independent on Ca(2+)/calmodulin.

Domain organisation. The autoinhibitory domain overlaps with the calmodulin binding region and may be involved in intrasteric autoinhibition. The RP domain (arginine/proline-rich) is involved in the recognition of CAMKI and CAMK4 as substrates.

Induction. Up-regulated by PKA pathway.

Miscellaneous. Major isoform. Major isoform. Inactive. Does not activate CAMK1 and CAMK4. Inactive. Does not activate CAMK1 and CAMK4.

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

Isoforms (7)

UniProt ID	Names	Canonical?
Q96RR4-1	1, Beta1, CAMKK2+E16	yes
Q96RR4-2	2, Beta2
Q96RR4-3	3, Beta1delta16, CAMKK2-E16
Q96RR4-4	4, Beta1delta14
Q96RR4-5	5, Beta1delta14/16, beta-3x
Q96RR4-6	6, Beta2delta14
Q96RR4-7	7

RefSeq proteins (9): NP_001257414, NP_001257415, NP_006540, NP_705719, NP_705720, NP_757363, NP_757364, NP_757365, NP_757380 (=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 (77 total): strand 12, helix 12, modified residue 11, region of interest 8, splice variant 8, sequence variant 7, sequence conflict 6, compositionally biased region 4, turn 3, binding site 2, initiator methionine 1, chain 1, active site 1, domain 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
6Y3O	X-RAY DIFFRACTION	1.5
6Y8A	X-RAY DIFFRACTION	1.5
8TUC	X-RAY DIFFRACTION	1.5
5UYJ	X-RAY DIFFRACTION	1.6
5UY6	X-RAY DIFFRACTION	1.7
6BQQ	X-RAY DIFFRACTION	1.8
5VT1	X-RAY DIFFRACTION	1.9
6BLE	X-RAY DIFFRACTION	1.9
5YV8	X-RAY DIFFRACTION	1.93
6BQP	X-RAY DIFFRACTION	1.95
6BKU	X-RAY DIFFRACTION	2
6BQL	X-RAY DIFFRACTION	2
5YVB	X-RAY DIFFRACTION	2.02
5YVC	X-RAY DIFFRACTION	2.02
6BRC	X-RAY DIFFRACTION	2.2
2ZV2	X-RAY DIFFRACTION	2.4
6CMJ	X-RAY DIFFRACTION	2.4
6EF5	X-RAY DIFFRACTION	2.44
5YV9	X-RAY DIFFRACTION	2.53
5YVA	X-RAY DIFFRACTION	2.57
6EWW	X-RAY DIFFRACTION	2.68
6FEL	X-RAY DIFFRACTION	2.84
6Y4K	X-RAY DIFFRACTION	3
6Y6B	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RR4-F1	67.93	0.39

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): 312 (proton acceptor)

Ligand- & substrate-binding residues (2): 171–179; 194

Post-translational modifications (11): 2, 100, 114, 129, 133, 137, 495, 511, 572, 522, 479

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-111932	CaMK IV-mediated phosphorylation of CREB
R-HSA-442729	CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde
R-HSA-9619229	Activation of RAC1 downstream of NMDARs
R-HSA-9619483	Activation of AMPK downstream of NMDARs
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-162582	Signal Transduction
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-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 256 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_REGULATION_OF_AUTOPHAGY, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, REACTOME_CREB1_PHOSPHORYLATION_THROUGH_THE_ACTIVATION_OF_CAMKII_CAMKK_CAMKIV_CASCASDE, GOBP_REGULATION_OF_PHOSPHORYLATION, RORA1_01, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, MORF_HDAC2, LUCAS_HNF4A_TARGETS_UP, CTATGCA_MIR153, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, STARK_HYPPOCAMPUS_22Q11_DELETION_UP, MARTINEZ_RB1_TARGETS_UP, RICKMAN_METASTASIS_DN, BOYLAN_MULTIPLE_MYELOMA_D_CLUSTER_DN

GO Biological Process (9): MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), calcium-mediated signaling (GO:0019722), cellular response to reactive oxygen species (GO:0034614), regulation of protein kinase activity (GO:0045859), positive regulation of DNA-templated transcription (GO:0045893), protein autophosphorylation (GO:0046777), CAMKK-AMPK signaling cascade (GO:0061762), positive regulation of autophagy of mitochondrion (GO:1903599)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), calcium/calmodulin-dependent protein kinase activity (GO:0004683), protein tyrosine kinase activity (GO:0004713), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytosol (GO:0005829), neuron projection (GO:0043005), nucleus (GO:0005634), cytoplasm (GO:0005737), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Post NMDA receptor activation events	3
Calmodulin induced 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
Intracellular signaling by second messengers	1
Signal Transduction	1
Signaling by GPCR	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	4
cellular anatomical structure	4
intracellular signaling cassette	2
phosphorylation	1
protein modification process	1
response to reactive oxygen species	1
cellular response to oxidative stress	1
cellular response to oxygen-containing compound	1
regulation of protein phosphorylation	1
regulation of kinase activity	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
protein phosphorylation	1
AMP-activated protein kinase activity	1
calcium/calmodulin-dependent protein kinase activity	1
calcium ion binding	1
calmodulin binding	1
calcium-mediated signaling	1
autophagy of mitochondrion	1
positive regulation of autophagy	1
regulation of autophagy of mitochondrion	1
protein serine/threonine kinase activity	1
metal ion binding	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
nuclear lumen	1
cytoplasm	1
plasma membrane bounded cell projection	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1606 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAMKK2	CALM1	P02593	986
CAMKK2	CALML3	P27482	981
CAMKK2	CALML5	Q9NZT1	981
CAMKK2	CALML6	Q8TD86	979
CAMKK2	CALML4	Q96GE6	979
CAMKK2	MTOR	P42345	746
CAMKK2	ADIPOR1	Q96A54	710
CAMKK2	PRKAB2	O43741	697
CAMKK2	PPARGC1A	Q9UBK2	696
CAMKK2	PRKAG2	Q9UGJ0	663
CAMKK2	RPTOR	Q8N122	660
CAMKK2	ADIPOR2	Q86V24	652
CAMKK2	SIRT1	Q96EB6	642
CAMKK2	PRKAB1	Q9Y478	607
CAMKK2	ADIPOQ	Q15848	606

IntAct

42 interactions, top by confidence:

A	B	Type	Score
FKBP5	IKBKB	psi-mi:“MI:0914”(association)	0.640
CAMKK2	OBSL1	psi-mi:“MI:0914”(association)	0.640
INSYN2A	CHUK	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
SFN	OXSR1	psi-mi:“MI:0914”(association)	0.530
CAMKK2	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CAMKK2	VIM	psi-mi:“MI:0915”(physical association)	0.400
HSP90AB1	CAMKK2	psi-mi:“MI:0915”(physical association)	0.400
	SGK1	psi-mi:“MI:0914”(association)	0.350
	PLK4	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AHRR	psi-mi:“MI:0914”(association)	0.350
	PAK4	psi-mi:“MI:0914”(association)	0.350
CAMK4	CNOT1	psi-mi:“MI:0914”(association)	0.350
CAMKK2	FEZF1	psi-mi:“MI:0914”(association)	0.350
CAMKK2	ESYT2	psi-mi:“MI:0914”(association)	0.350
CALM1	MYO1C	psi-mi:“MI:0914”(association)	0.350
CALM2	MYO1C	psi-mi:“MI:0914”(association)	0.350
CALM3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
C6orf141	KRBA1	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
FILIP1	DAPK3	psi-mi:“MI:0914”(association)	0.350
MAPK14	PRKY	psi-mi:“MI:0914”(association)	0.350
HINT1	OGA	psi-mi:“MI:0914”(association)	0.350
GCHFR	OBSL1	psi-mi:“MI:0914”(association)	0.350
MYL4	MYL1	psi-mi:“MI:0914”(association)	0.350
ATG7	IFT56	psi-mi:“MI:0914”(association)	0.350

BioGRID (88): CAMKK2 (Affinity Capture-MS), CAMKK2 (Reconstituted Complex), CAMKK2 (Affinity Capture-MS), CAMKK2 (Affinity Capture-MS), CAMKK2 (Affinity Capture-MS), CAMKK2 (Affinity Capture-MS), CAMKK2 (Affinity Capture-MS), CAMKK2 (Affinity Capture-RNA), CAMKK2 (Affinity Capture-Western), CAMKK2 (Affinity Capture-MS), CAMKK2 (Affinity Capture-MS), CAMKK2 (Proximity Label-MS), CAMKK2 (Proximity Label-MS), CAMKK2 (Biochemical Activity), CAMKK2 (Biochemical Activity)

ESM2 similar proteins: A0AUV4, A1A5Q6, A1A5R7, A2KF29, B1WAS2, C0HKC8, C0HKC9, D3ZML2, O60285, O74536, O88831, O88866, P41279, P51956, P57058, P97756, Q20443, Q2T9U5, Q5R7G9, Q5XHI9, Q60670, Q63562, Q641K5, Q66HE5, Q68UT7, Q6P431, Q6VZ17, Q7T0B0, Q7T0B1, Q7TNJ7, Q7TNL4, Q8BHI9, Q8BZN4, Q8C078, Q8C0N0, Q8C0V7, Q8C0X8, Q8CIP4, Q8IY84, Q8K4K4

Diamond homologs: A2XFF4, A3B529, A6ZU08, A8WYE4, A8X0C4, B3DL84, B4J3F1, B4KYX8, B4LDJ6, B8BBT7, D4AE59, F1QGZ6, O08679, O14965, O22932, O55099, O59790, O70126, O88445, O88831, P25341, P25389, P32801, P38990, P43637, P50526, P54645, P59241, P92958, P97756, Q05512, Q0D4B2, Q0GGW5, Q0JI49, Q10SC8, Q12263, Q13131, Q14680, Q15831, Q16W24

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
DAPK1	down-regulates	CAMKK2	phosphorylation
DAPK1	unknown	CAMKK2	phosphorylation
CAMKK2	up-regulates	PRKAA2	phosphorylation
CAMKK2	up-regulates	PRKAA1	phosphorylation
CDK5	down-regulates	CAMKK2	phosphorylation
CAMKK2	up-regulates	CAMKK2	phosphorylation
GSK3A	down-regulates	CAMKK2	phosphorylation
GSK3B	down-regulates	CAMKK2	phosphorylation
PKA	down-regulates	CAMKK2	phosphorylation
CAMKK2	up-regulates	AMPK	phosphorylation
CALM2	up-regulates	CAMKK2	binding
CALM3	up-regulates	CAMKK2	binding
CALM1	up-regulates	CAMKK2	binding
CAMKK2	“up-regulates activity”	CAMK1	phosphorylation
CAMKK2	“up-regulates activity”	CAMK4	phosphorylation
PKA	“down-regulates activity”	CAMKK2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Innate Immune System	8	5.5×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	6	7.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	9
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

3054 predictions. Top by Δscore:

Variant	Effect	Δscore
12:121244626:C:CT	acceptor_gain	1.0000
12:121245136:TCA:T	donor_loss	1.0000
12:121245137:CAC:C	donor_loss	1.0000
12:121245138:A:AC	donor_gain	1.0000
12:121245138:ACG:A	donor_loss	1.0000
12:121245139:C:CA	donor_gain	1.0000
12:121245139:CG:C	donor_gain	1.0000
12:121245139:CGT:C	donor_gain	1.0000
12:121245139:CGTG:C	donor_gain	1.0000
12:121245139:CGTGA:C	donor_gain	1.0000
12:121245237:GGAT:G	acceptor_gain	1.0000
12:121245238:GAT:G	acceptor_gain	1.0000
12:121245241:C:CC	acceptor_gain	1.0000
12:121245242:T:C	acceptor_loss	1.0000
12:121249782:GGTAC:G	donor_loss	1.0000
12:121249783:GTAC:G	donor_loss	1.0000
12:121249784:TA:T	donor_loss	1.0000
12:121249786:C:CA	donor_loss	1.0000
12:121249952:GATAC:G	donor_loss	1.0000
12:121249953:ATACT:A	donor_loss	1.0000
12:121249955:AC:A	donor_loss	1.0000
12:121249957:TCAC:T	donor_loss	1.0000
12:121249958:CA:C	donor_loss	1.0000
12:121249959:A:AC	donor_gain	1.0000
12:121249959:AC:A	donor_loss	1.0000
12:121249960:C:CT	donor_gain	1.0000
12:121249960:CTG:C	donor_gain	1.0000
12:121249960:CTGG:C	donor_gain	1.0000
12:121249960:CTGGT:C	donor_gain	1.0000
12:121250030:GGGCA:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002040 (12:121293020 A>G), RS1000022043 (12:121289807 C>A,T), RS1000047916 (12:121248896 G>A), RS1000137137 (12:121269021 G>A), RS1000321622 (12:121250095 C>T), RS1000364688 (12:121254266 T>C), RS1000383285 (12:121244392 G>A), RS1000434121 (12:121244628 G>A), RS1000487040 (12:121284392 T>C), RS1000531498 (12:121296336 G>C), RS1000546711 (12:121239994 C>A), RS1000556147 (12:121287656 A>G), RS1000602576 (12:121283220 T>C,G), RS1000640102 (12:121291341 C>T), RS1000655049 (12:121283023 G>A)

Disease associations

OMIM: gene MIM:615002 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004719_15	Left ventricular obstructive tract defect (inherited effect)	4.000000e-06
GCST005414_21	Type 2 diabetes	4.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5284 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

42 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 225,941 (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
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1738797	ALECTINIB	4	6,731
CHEMBL2035187	PACRITINIB	4	3,345
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301607	FILGOTINIB	4	2,905
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL1233528	VOLASERTIB	3	1,511
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3
CHEMBL1230609	FORETINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL3655762	CYC-065	2
CHEMBL384304	RG-547	2
CHEMBL402548	DANUSERTIB	2
CHEMBL445813	AT-7519	2
CHEMBL513909	BI-2536	2
CHEMBL564829	MILCICLIB	2

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1653586	CAMKK2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Meta subfamily

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
STO609	Inhibition	7.4	pIC50

Binding affinities (BindingDB)

12 measured of 13 human assays (13 total across all organisms); most potent 12 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Staurosporine	KD	1.7 nM
4-[[4-cyclopentyloxy-5-[4-(methylcarbamoyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-methylbenzamide	IC50	34 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
PKC-412	KD	190 nM
4-[[4-cyclopentyloxy-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-N-(2-hydroxyethyl)-3-methoxybenzamide	IC50	501 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
4-[[4-cyclopentyloxy-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxy-N-methylbenzamide	IC50	728 nM	US-9623028: Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 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
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

249 potent at pChembl≥5 of 257 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.30	Kd	0.05	nM	STAUROSPORINE
9.80	Kd	0.16	nM	STAUROSPORINE
9.70	Ki	0.2	nM	STAUROSPORINE
9.70	Ki	0.1995	nM	CHEMBL1980995
9.52	IC50	0.3	nM	STAUROSPORINE
8.90	Ki	1.259	nM	CHEMBL458997
8.90	Ki	1.259	nM	CHEMBL1993661
8.85	IC50	1.4	nM	CHEMBL5421767
8.80	IC50	1.585	nM	CHEMBL4126095
8.74	Ki	1.8	nM	CHEMBL416056
8.70	IC50	1.995	nM	CHEMBL4128577
8.70	IC50	1.995	nM	CHEMBL4129590
8.70	Kd	2	nM	CHEMBL4465866
8.64	IC50	2.3	nM	GSK-650394
8.60	IC50	2.5	nM	CHEMBL5439578
8.52	IC50	3	nM	GSK-650394
8.40	IC50	3.981	nM	CHEMBL4127245
8.40	IC50	4	nM	CHEMBL5431962
8.30	IC50	5	nM	CHEMBL4875005
8.22	Kd	6	nM	CHEMBL4576489
8.20	IC50	6.31	nM	CHEMBL4128540
8.15	IC50	7	nM	CHEMBL5426746
8.15	IC50	7	nM	CHEMBL5396413
8.14	IC50	7.3	nM	CHEMBL5421767
8.10	IC50	7.943	nM	GSK-650394
8.10	IC50	7.943	nM	CHEMBL4126511
8.10	IC50	7.943	nM	CHEMBL4129219
8.09	IC50	8.1	nM	CHEMBL4870467
8.05	IC50	9	nM	CHEMBL5422255
8.00	IC50	10	nM	CHEMBL265470
7.96	Kd	11	nM	TAE-684
7.92	IC50	12	nM	CHEMBL4849143
7.90	IC50	12.59	nM	CHEMBL4128459
7.90	IC50	12.59	nM	CHEMBL4128939
7.90	IC50	12.59	nM	CHEMBL4127977
7.90	IC50	12.59	nM	CHEMBL4128114
7.90	IC50	12.59	nM	CHEMBL4126740
7.90	IC50	12.59	nM	CHEMBL4127140
7.89	IC50	13	nM	CHEMBL4852523
7.82	Ki	15	nM	CHEMBL1908392
7.82	Kd	15	nM	LESTAURTINIB
7.80	IC50	15.85	nM	CHEMBL4128717
7.80	IC50	15.85	nM	CHEMBL4127330
7.80	IC50	15.85	nM	CHEMBL4127064
7.80	IC50	15.7	nM	STAUROSPORINE
7.70	IC50	19.95	nM	CHEMBL550110
7.70	IC50	19.95	nM	CHEMBL4129791
7.70	IC50	19.95	nM	CHEMBL4129362
7.70	IC50	19.95	nM	CHEMBL4129843
7.68	Kd	21	nM	CHEMBL4752776

PubChem BioAssay actives

219 with measured affinity, of 1232 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	256580: Average Binding Constant for CAMKK2; NA=Not Active at 10 uM	kd	0.0001	uM
4-(7-ethoxyquinazolin-4-yl)-2-propan-2-ylbenzoic acid	2023207: Inhibition of CaMKK2 (161 to 449 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) star cells incubated for 20 mins in presence of kinase tracer 236 by TR-FRET	ic50	0.0014	uM
4-[2-[2-methyl-4-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0016	uM
methyl (15R,16S,18S)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	325589: Inhibition of CaM-KKbeta	ki	0.0018	uM
2-cyclopentyl-4-[2-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0020	uM
4-[2-(2-methoxyanilino)pyrimidin-4-yl]-2-propan-2-ylbenzoic acid	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0020	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526154: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged CAMKK2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr in presence of calmodulin by TR-FRET assay	kd	0.0020	uM
2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid	2023207: Inhibition of CaMKK2 (161 to 449 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) star cells incubated for 20 mins in presence of kinase tracer 236 by TR-FRET	ic50	0.0023	uM
2-cyclopentyl-4-(7-ethoxy-5-fluoroquinazolin-4-yl)benzoic acid	2023207: Inhibition of CaMKK2 (161 to 449 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) star cells incubated for 20 mins in presence of kinase tracer 236 by TR-FRET	ic50	0.0025	uM
4-(2-anilinopyrimidin-4-yl)-2-cyclopentylbenzoic acid	1768402: Inhibition of NanoLuc-fused CAMKK2 (unknown origin) expressed in HEK293 cells after 24 hrs by NanoBRET assay	ic50	0.0030	uM
4-(7-ethoxy-5-fluoroquinazolin-4-yl)-2-propan-2-ylbenzoic acid	2023207: Inhibition of CaMKK2 (161 to 449 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) star cells incubated for 20 mins in presence of kinase tracer 236 by TR-FRET	ic50	0.0040	uM
4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-propan-2-ylbenzoic acid	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0040	uM
2-cyclopentyl-4-(5-phenylthieno[2,3-b]pyridin-3-yl)benzoic acid	1768357: Inhibition of human CAMKK2 using CAMKKtide as substrate assessed as residual activity by [gamma-33P]-ATP assay relative to control	ic50	0.0050	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	1526154: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged CAMKK2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr in presence of calmodulin by TR-FRET assay	kd	0.0060	uM
4-[2-[2-methyl-4-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-propan-2-ylbenzonitrile	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0063	uM
2-cyclopentyl-4-(7-ethoxyquinazolin-4-yl)benzoic acid	2023207: Inhibition of CaMKK2 (161 to 449 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) star cells incubated for 20 mins in presence of kinase tracer 236 by TR-FRET	ic50	0.0070	uM
2-cyclopentyl-4-(7-ethoxy-6-fluoroquinazolin-4-yl)benzoic acid	2023207: Inhibition of CaMKK2 (161 to 449 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) star cells incubated for 20 mins in presence of kinase tracer 236 by TR-FRET	ic50	0.0070	uM
4-[5-fluoro-2-(2-methoxyanilino)pyrimidin-4-yl]-2-propan-2-ylbenzoic acid	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0079	uM
4-[2-[2-methyl-4-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-propan-2-ylbenzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0079	uM
2-cyclopentyl-4-(2-phenyl-1H-imidazo[4,5-b]pyridin-7-yl)benzoic acid	1768402: Inhibition of NanoLuc-fused CAMKK2 (unknown origin) expressed in HEK293 cells after 24 hrs by NanoBRET assay	ic50	0.0081	uM
2-cyclopentyl-4-[7-[10-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-10-oxodecoxy]quinazolin-4-yl]benzoic acid	2023207: Inhibition of CaMKK2 (161 to 449 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) star cells incubated for 20 mins in presence of kinase tracer 236 by TR-FRET	ic50	0.0090	uM
acetic acid;11-oxo-3,10-diazapentacyclo[10.7.1.02,10.04,9.016,20]icosa-1(20),2,4,6,8,12,14,16,18-nonaene-17-carboxylic acid	435333: Inhibition of CAMKKbeta in the presence of 20uM ATP	ic50	0.0100	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	625060: Binding constant for CAMKK2 kinase domain	kd	0.0110	uM
2-cyclopentyl-4-(6-phenylquinazolin-4-yl)benzoic acid	1768357: Inhibition of human CAMKK2 using CAMKKtide as substrate assessed as residual activity by [gamma-33P]-ATP assay relative to control	ic50	0.0120	uM
4-[2-[2-methyl-5-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-propan-2-ylbenzonitrile	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0126	uM
4-[2-[3-(methanesulfonamido)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0126	uM
4-[2-[2-methyl-3-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0126	uM
3-[4-(4-carbamoylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-N-[3-(dimethylamino)propyl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0126	uM
4-[2-[4-(methanesulfonamido)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0126	uM
4-[2-[4-[3-(dimethylamino)propylcarbamoyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0126	uM
2-cyclopentyl-4-quinolin-4-ylbenzoic acid	1768357: Inhibition of human CAMKK2 using CAMKKtide as substrate assessed as residual activity by [gamma-33P]-ATP assay relative to control	ic50	0.0130	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	507861: Binding affinity to CAMKK2	kd	0.0150	uM
N-[4-[[(2-hydroxy-1H-indol-3-yl)-phenylmethylidene]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide	1474639: Inhibition of CAMKK2 (unknown origin) using NUAK2 peptide as substrate measured after 30 mins in presence of [gamma32P]ATP by liquid scintillation counting method	ki	0.0150	uM
4-[2-[2-methyl-3-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0158	uM
4-[2-[2-methyl-5-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0158	uM
4-(6-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopentylbenzoic acid	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0158	uM
4-[2-[2-methyl-5-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-2-propan-2-ylbenzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0199	uM
4-[2-(2-fluoro-5-phenylanilino)pyrimidin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0199	uM
4-[2-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0199	uM
2-ethyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0199	uM
2-[6-(1-benzothiophen-2-yl)thieno[3,2-d]pyrimidin-4-yl]sulfanylacetic acid	1718394: Binding affinity to human CAMKK2 assessed as displacement of immobilized ligand by KINOMEscan scanMAX assay relative to control	kd	0.0210	uM
2-cyclopentyl-4-pyrimidin-4-ylbenzoic acid	1768357: Inhibition of human CAMKK2 using CAMKKtide as substrate assessed as residual activity by [gamma-33P]-ATP assay relative to control	ic50	0.0210	uM
2-cyclopentyl-4-(5-phenylpyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid	1768357: Inhibition of human CAMKK2 using CAMKKtide as substrate assessed as residual activity by [gamma-33P]-ATP assay relative to control	ic50	0.0210	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	625060: Binding constant for CAMKK2 kinase domain	kd	0.0230	uM
2-cyclopentyl-4-thieno[3,2-d]pyrimidin-4-ylbenzoic acid	1768357: Inhibition of human CAMKK2 using CAMKKtide as substrate assessed as residual activity by [gamma-33P]-ATP assay relative to control	ic50	0.0240	uM
4-[2-(3-phenylanilino)pyrimidin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0251	uM
4-[2-[4-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0251	uM
4-[2-[2-methyl-4-(morpholin-4-ylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]benzamide	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0251	uM
2-(2-methylpropyl)-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid	1494993: Inhibition of full-length human GST-tagged CAMKK2 using 5FAM-AKPKGNKDYHLQTCCGSLAYRRR-amide as substrate preincubated for 30 mins followed by substrate addition measured after 120 mins by fluorescence polarization assay	ic50	0.0251	uM
2-cyclopentyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid	1768357: Inhibition of human CAMKK2 using CAMKKtide as substrate assessed as residual activity by [gamma-33P]-ATP assay relative to control	ic50	0.0260	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Cisplatin	decreases expression, increases expression	2
Estradiol	increases expression	2
Dihydrotestosterone	affects localization, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
coumarin	increases phosphorylation	1
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole	decreases reaction, increases phosphorylation	1
1,2-bis(2-aminophenoxy)ethane N,N,N’,N’-tetraacetic acid acetoxymethyl ester	decreases reaction, increases phosphorylation	1
4-phenylbutyric acid	increases expression, decreases reaction	1
platycodin D	decreases reaction, increases phosphorylation	1
STO 609	decreases activity	1
abrine	decreases expression	1
PX-866	affects response to substance	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	increases phosphorylation, decreases reaction	1
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	decreases reaction, increases phosphorylation	1
Cidofovir	increases expression	1
Air Pollutants	affects expression, increases abundance	1
alpha-Chlorohydrin	decreases reaction, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Calcitriol	affects localization, decreases reaction	1
Calcium	affects cotreatment, affects reaction, increases phosphorylation	1

ChEMBL screening assays

320 unique, capped per target: 319 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000629	Binding	Inhibition of CAMKKb at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL1963755	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CAMKK2	PubChem BioAssay data set

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_B2TE	Abcam HEK293T CAMKK2 KO	Transformed cell line	Female
CVCL_D7LM	Ubigene A-549 CAMKK2 KO	Cancer cell line	Male
CVCL_D8IE	Ubigene HCT 116 CAMKK2 KO	Cancer cell line	Male
CVCL_D9ZB	Ubigene HeLa CAMKK2 KO	Cancer cell line	Female
CVCL_F1Q4	HyCyte Hep-G2 KO-hCAMKK2	Cancer cell line	Male
CVCL_SG71	HAP1 CAMKK2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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