PRKAA2

Summary

PRKAA2 (protein kinase AMP-activated catalytic subunit alpha 2, HGNC:9377) is a protein-coding gene on chromosome 1p32.2, encoding 5’-AMP-activated protein kinase catalytic subunit alpha-2 (P54646). Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In precision oncology, PRKAA2 T172 PHOSPHORYLATION confers sensitivity to ACLY SiRNA in Cancer (CIViC Level E).

The protein encoded by this gene is a catalytic subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. Studies of the mouse counterpart suggest that this catalytic subunit may control whole-body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia.

Source: NCBI Gene 5563 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 72 total
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_006252

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9377
Approved symbol	PRKAA2
Name	protein kinase AMP-activated catalytic subunit alpha 2
Location	1p32.2
Locus type	gene with protein product
Status	Approved
Aliases	AMPK, AMPKa2
Ensembl gene	ENSG00000162409
Ensembl biotype	protein_coding
OMIM	600497
Entrez	5563

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000371244, ENST00000860136, ENST00000860137, ENST00000860138

RefSeq mRNA: 1 — MANE Select: NM_006252 NM_006252

CCDS: CCDS605

Canonical transcript exons

ENST00000371244 — 9 exons

Exon	Start	End
ENSE00001064887	56691394	56691487
ENSE00001064889	56695935	56696159
ENSE00001064891	56703971	56704475
ENSE00001064893	56693765	56693852
ENSE00001064895	56674381	56674522
ENSE00001064897	56706092	56706218
ENSE00001064901	56692358	56692502
ENSE00001454729	56707475	56715335
ENSE00001454737	56645314	56645481

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 98.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6380 / max 208.1324, expressed in 948 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2995	5.9968	911
2994	0.4951	271
2992	0.0937	51
2993	0.0523	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.38	gold quality
biceps brachii	UBERON:0001507	97.82	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.64	gold quality
heart right ventricle	UBERON:0002080	97.01	gold quality
body of tongue	UBERON:0011876	93.22	gold quality
renal medulla	UBERON:0000362	92.20	gold quality
saphenous vein	UBERON:0007318	91.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.74	gold quality
vena cava	UBERON:0004087	90.53	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.35	gold quality
gastrocnemius	UBERON:0001388	90.03	gold quality
muscle of leg	UBERON:0001383	89.49	gold quality
muscle organ	UBERON:0001630	88.77	gold quality
tongue	UBERON:0001723	88.51	gold quality
cardiac ventricle	UBERON:0002082	88.30	gold quality
heart left ventricle	UBERON:0002084	88.01	gold quality
skeletal muscle tissue	UBERON:0001134	87.90	gold quality
endothelial cell	CL:0000115	87.88	gold quality
superior surface of tongue	UBERON:0007371	87.66	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.84	gold quality
heart	UBERON:0000948	86.24	gold quality
middle temporal gyrus	UBERON:0002771	86.23	gold quality
vastus lateralis	UBERON:0001379	86.13	gold quality
quadriceps femoris	UBERON:0001377	85.88	gold quality
cardia of stomach	UBERON:0001162	85.70	gold quality
myocardium	UBERON:0002349	85.42	gold quality
muscle tissue	UBERON:0002385	85.23	gold quality
right atrium auricular region	UBERON:0006631	85.06	gold quality
deltoid	UBERON:0001476	85.05	gold quality
cardiac atrium	UBERON:0002081	84.94	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.09

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
EIF4E	Repression
EIF4G1	Repression
HDAC6	Repression

Upstream regulators (CollecTRI, top): FOXO3, HNF4A, MEF2A, NFKB, NR0B2, SON

miRNA regulators (miRDB)

372 targeting PRKAA2, 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-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
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-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3185	99.99	68.12	1959

Literature-anchored findings (GeneRIF, showing 40)

• Hepatic amino acid-dependent signaling is under the control of AMP-dependent protein kinase. (PMID:12067722)
• Role of AMPK in tolerance to glucose starvation in cell lines (PMID:12091379)
• AMPK signaling is not a key regulatory system of muscle substrate combustion during prolonged exercise and marked activation of AMPK via phosphorylation is not sufficient to maintain an elevated ACCbeta Ser(221) phosphorylation during prolonged exercise (PMID:12413941)
• Regulation of channel gating by AMP-activated protein kinase modulates cystic fibrosis transmembrane conductance regulator activity in lung submucosal cells. (PMID:12427743)
• Overexpression of mutant AMPK-alpha1 enhanced forskolin-stimulated I short-circuit currents, consistent with dominant-negative reduction in inhibition of CFTR by endogenous AMPK. (PMID:12519745)
• results suggest that nuclear translocation of 5’ AMP-activated protein kinase might mediate the effects of exercise on skeletal muscle gene and protein expression (PMID:12663462)
• endothelial AMPK signaling may be a critical determinant of blood vessel recruitment to tissues that are subjected to ischemic stress. (PMID:12788940)
• LKB1 kinase, which is associated with Peutz-Jeghers cancer-susceptibility syndrome, phosphorylates and activates AMPK in vitro. (PMID:12847291)
• Acetyl-CoA carboxylase beta phosphorylation is especially sensitive to exercise and tightly coupled to AMPK signaling and that AMPK activation does not depend on AMPK kinase activation during exercise. (PMID:12941758)
• This study demonstrates that protein content and basal AMPK activity in human skeletal muscle are highly susceptible to endurance exercise training. (PMID:14613924)
• AMPK and eEF2 kinase may provide a key link between cellular energy status and the inhibition of protein synthesis, a major consumer of metabolic energy (PMID:14709557)
• AMPK is a major regulator of skeletal muscle HSL activity that can override beta-adrenergic stimulation (PMID:15231718)
• AMPK is a novel and critical component of HIF-1 regulation, implying its involvement in vanadate-induced prostate carcinogenesis (PMID:15297373)
• Results indicate that AMP-activated protein kinase (AMPK)alpha negatively regulates acetyl-CoA carboxylase activity and hepatic lipid content. (PMID:15371448)
• AMPK has a role in the phenobarbital induction of CYP2B gene expression (PMID:15572372)
• 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)
• causes inappropriate AMP kinase activation, which leads to glycogen accumulation and heart conduction system disease when transfected into mice (PMID:16275868)
• data suggest that moderate endurance exercise promotes glucose transport, GLUT4 expression, and insulin sensitivity in skeletal muscle at least partially via activation of the alpha2 isoform of AMPK (PMID:16483872)
• These data suggest that prolonged hypoxia promotes the expression and functional activation of AMPKalpha2 and VEGF production in glioma cell lines and glioblastoma multiform tumors, thus contributing to tumor survival and angiogenesis in gliomas. (PMID:16518831)
• PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population. (PMID:16567511)
• Oral glucose ingestion attenuates the exercise-induced activation of alpha2-AMPK, bringing further support for a fuel-sensing role of AMPK in skeletal muscle. (PMID:16598851)
• Findings indicate that AMPK activation in skeletal muscle during exercise is not sensitive to changes in plasma glucose levels in the normal range. (PMID:16670154)
• AA454543 may have a role in progression of hepatocellular carcinoma after partial hepatectomy (PMID:16984726)
• AMPK has a central role in stimulus-response coupling by hypoxia (PMID:17179156)
• genetic variants of LKB1-AMPK-TORC2 pathway components may exert a weak influence on the occurrence of type 2 diabetes in Japanese (PMID:17950019)
• alpha2 But not alpha1 AMP-activated protein kinase mediates oxidative stress-induced inhibition of retinal pigment epithelium cell phagocytosis of photoreceptor outer segments (PMID:18195011)
• AMPK alpha2 activity, AMPK alpha2 Thr172 phosphorylation, and ACC-beta Ser222 phosphorylation were increased immediately after exercise. These increases had all returned to basal levels at 3 and 24 h after exercise. (PMID:18614941)
• Results demonstrate that AMPK-alpha1 and AMPK-alpha2 activity and fuel selection in skeletal muscle in response to exercise can be manipulated by diet and/or the interactive effects of diet and exercise training. (PMID:18801964)
• A novel AMPK-mediated regulatory pathway that regulates PGC-1alpha gene expression. (PMID:18974883)
• The phosphorylation of GFAT1 at Ser243 by AMPK has an important role in the regulation of the GFAT1 enzymatic activity. (PMID:19170765)
• Inhibition of de novo purine synthesis in human prostate cells results in ATP depletion, AMPK and p53 activation, and induces senescence. (PMID:19434633)
• resistin induces insulin resistance in HepG2 cells at least partly via induction of SOCS-3 expression and reduction of Akt phosphorylation through an AMPK-independent mechanism (PMID:19440859)
• Treatment with globular adiponectin significantly reduced simulated ischemia-reperfusion injury induced apoptosis in WT cardiomyocytes as well as in AMPK-alpha2 dominant negative cardiomyocytes. (PMID:19470831)
• Results suggest that fatty acids and ER stress reduce AdipoR2 protein and pAMPK levels. (PMID:19502591)
• Results suggest that the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues. (PMID:19528236)
• Variants in genes for AMPKalpha2 and AMPKgamma3 were not associated with PCOS or its component traits. (PMID:19574280)
• a novel signaling pathway inhibits hepatic gluconeogenesis through HGF/AMPK/USF-1/SHP (PMID:19720831)
• Data suggest that genistein in combination with capsaicin exerts anti-inflammatory and anticarcinogenic properties through the modulation of AMPK and COX-2 and possibly various mitogen-activated protein kinases synergistically or nonsynergistically. (PMID:19723084)
• These results indicate that AMP-activated protein kinase supports the NGF-induced viability of human HeLa cells to glucose starvation. (PMID:19728147)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkaa2	ENSDARG00000060641
mus_musculus	Prkaa2	ENSMUSG00000028518
rattus_norvegicus	Prkaa2	ENSRNOG00000007706
drosophila_melanogaster	AMPKalpha	FBGN0023169
caenorhabditis_elegans		WBGENE00012638
caenorhabditis_elegans	tag-344	WBGENE00015230
caenorhabditis_elegans		WBGENE00044388

Paralogs (17): NUAK1 (ENSG00000074590), PRKAA1 (ENSG00000132356), TSSK4 (ENSG00000139908), HUNK (ENSG00000142149), SIK1 (ENSG00000142178), BRSK1 (ENSG00000160469), SIK3 (ENSG00000160584), TSSK3 (ENSG00000162526), NUAK2 (ENSG00000163545), SNRK (ENSG00000163788), MELK (ENSG00000165304), SIK2 (ENSG00000170145), BRSK2 (ENSG00000174672), NIM1K (ENSG00000177453), TSSK6 (ENSG00000178093), TSSK2 (ENSG00000206203), TSSK1B (ENSG00000212122)

Protein

Protein identifiers

5’-AMP-activated protein kinase catalytic subunit alpha-2 — P54646 (reviewed: P54646)

Alternative names: Acetyl-CoA carboxylase kinase, Hydroxymethylglutaryl-CoA reductase kinase

All UniProt accessions (1): P54646

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. Involved in insulin receptor/INSR internalization. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates ‘Ser-36’ of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24 and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. Also phosphorylates and inhibits GATOR2 subunit WDR24 in response to nutrient limitation, leading to suppress glucose-mediated mTORC1 activation. In response to energetic stress, phosphorylates FNIP1, inactivating the non-canonical mTORC1 signaling, thereby promoting nuclear translocation of TFEB and TFE3, and inducing transcription of lysosomal or autophagy genes. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. In that process, it also activates WDR45/WIPI4. Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1. Upon glucose starvation, promotes ARF6 activation in a kinase-independent manner leading to cell migration. Upon glucose deprivation mediates the phosphorylation of ACSS2 at ‘Ser-659’, which exposes the nuclear localization signal of ACSS2, required for its interaction with KPNA1 and nuclear translocation. Upon stress, regulates mitochondrial fragmentation through phosphorylation of MTFR1L.

Subunit / interactions. AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2. Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; PRKAA2/AMPK2 together with ATIC and HACD3/PTPLAD1 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis. Interacts with ARF6. The phosphorylated form at Thr-172 mediated by CamKK2 interacts with ACSS2.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Ubiquitinated. Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1).

Activity regulation. Activated by phosphorylation on Thr-172. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo. Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation.

Domain organisation. The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.

RefSeq proteins (1): NP_006243* (*=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
IPR028375	KA1/Ssp2_C	Homologous_superfamily
IPR028783	PRKAA2	Domain
IPR032270	AMPK_C	Domain
IPR039148	AMPKA2_C	Domain
IPR049020	PRKAA1/2_AID	Domain

Pfam: PF00069, PF16579, PF21147

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)
• EC 2.7.11.31 — [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase (BRENDA: 25 organisms, 266 substrates, 134 inhibitors, 51 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.02–0.4168	15
ATP	0.0007–0.64	11
BIOTIN-GGHMRSAMSGLHLVKRR-NH2	0.0267–0.1214	6
ACETYL-COA CARBOXYLASE	—	4
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
HMGSAMSGLHLVKRR	0.573–2.316	2
HMHSAMSGLHLVKRR	0.118–0.428	2
HMKSAMSGLHLVKRR	0.111–0.133	2
HMRSAGSGLHLVKRR	0.069–0.07	2
HMRSAMSGLHGVKRR	0.013–0.096	2
HMRSAMSGLHLGKRR	0.038–0.042	2
HMRSAMSGLHLVKRR	0.0498–0.091	2
HMRSAMTGLHGVKRR	0.034–0.065	2

Catalyzed reactions (Rhea), 4 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-seryl-[acetyl-CoA carboxylase] + ATP = O-phospho-L-seryl-[acetyl-CoA carboxylase] + ADP + H(+) (RHEA:20333)
• L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] + ATP = O-phospho-L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] + ADP + H(+) (RHEA:23172)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (60 total): helix 22, strand 13, modified residue 4, sequence variant 3, mutagenesis site 3, sequence conflict 3, compositionally biased region 3, region of interest 2, turn 2, binding site 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
2H6D	X-RAY DIFFRACTION	1.85
3AQV	X-RAY DIFFRACTION	2.08
8BIK	X-RAY DIFFRACTION	2.5
9IC2	X-RAY DIFFRACTION	2.5
5ISO	X-RAY DIFFRACTION	2.63
6B1U	X-RAY DIFFRACTION	2.77
6BX6	X-RAY DIFFRACTION	2.9
7MYJ	X-RAY DIFFRACTION	2.95
4ZHX	X-RAY DIFFRACTION	2.99
5EZV	X-RAY DIFFRACTION	2.99
2YZA	X-RAY DIFFRACTION	3.02
4CFE	X-RAY DIFFRACTION	3.02
6B2E	X-RAY DIFFRACTION	3.8
4CFF	X-RAY DIFFRACTION	3.92
2LTU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54646-F1	77.64	0.42

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): 139 (proton acceptor)

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

Post-translational modifications (4): 172, 258, 377, 491

Mutagenesis-validated functional residues (3):

Position	Phenotype
45	complete loss of kinase activity.
172	loss of arf6 activation. loss of interaction with acss2.
172	phosphomimetic mutant.

Function

Pathways and Gene Ontology

Reactome pathways

38 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-1632852	Macroautophagy
R-HSA-163680	AMPK inhibits chREBP transcriptional activation activity
R-HSA-200425	Carnitine shuttle
R-HSA-2151209	Activation of PPARGC1A (PGC-1alpha) by phosphorylation
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-9613354	Lipophagy
R-HSA-9619483	Activation of AMPK downstream of NMDARs
R-HSA-9759194	Nuclear events mediated by NFE2L2
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-163685	Integration of energy metabolism
R-HSA-165159	MTOR signalling
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-199991	Membrane Trafficking
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-438064	Post NMDA receptor activation events
R-HSA-442755	Activation of NMDA receptors and postsynaptic events
R-HSA-556833	Metabolism of lipids
R-HSA-5633007	Regulation of TP53 Activity
R-HSA-5653656	Vesicle-mediated transport

MSigDB gene sets: 453 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_PROSTAGLANDIN_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (57): fatty acid biosynthetic process (GO:0006633), cholesterol biosynthetic process (GO:0006695), autophagy (GO:0006914), signal transduction (GO:0007165), lipid biosynthetic process (GO:0008610), positive regulation of autophagy (GO:0010508), negative regulation of gene expression (GO:0010629), response to muscle activity (GO:0014850), Wnt signaling pathway (GO:0016055), positive regulation of macroautophagy (GO:0016239), regulation of macroautophagy (GO:0016241), cellular response to nutrient levels (GO:0031669), negative regulation of TOR signaling (GO:0032007), cellular response to oxidative stress (GO:0034599), cellular response to glucose starvation (GO:0042149), glucose homeostasis (GO:0042593), regulation of circadian rhythm (GO:0042752), negative regulation of apoptotic process (GO:0043066), positive regulation of glycolytic process (GO:0045821), rhythmic process (GO:0048511), fatty acid homeostasis (GO:0055089), regulation of stress granule assembly (GO:0062028), regulation of microtubule cytoskeleton organization (GO:0070507), cellular response to calcium ion (GO:0071277), cellular response to glucose stimulus (GO:0071333), cellular response to prostaglandin E stimulus (GO:0071380), cellular response to xenobiotic stimulus (GO:0071466), energy homeostasis (GO:0097009), positive regulation of protein localization (GO:1903829), negative regulation of hepatocyte apoptotic process (GO:1903944), negative regulation of TORC1 signaling (GO:1904262), negative regulation of tubulin deacetylation (GO:1904428), lipid droplet disassembly (GO:1905691), protein localization to lipid droplet (GO:1990044), cytoplasmic translation (GO:0002181), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), protein phosphorylation (GO:0006468), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (14): chromatin binding (GO:0003682), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), AMP-activated protein kinase activity (GO:0004679), protein serine/threonine/tyrosine kinase activity (GO:0004712), ATP binding (GO:0005524), metal ion binding (GO:0046872), [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity (GO:0047322), protein serine kinase activity (GO:0106310), histone H2BS36 kinase activity (GO:0140823), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (12): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), nuclear speck (GO:0016607), axon (GO:0030424), dendrite (GO:0030425), nucleotide-activated protein kinase complex (GO:0031588), ciliary basal body (GO:0036064), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Membrane Trafficking	1
Autophagy	1
Integration of energy metabolism	1
Fatty acid metabolism	1
Mitochondrial biogenesis	1
MTOR signalling	1
Transcriptional Regulation by TP53	1
Regulation of TP53 Activity	1
Selective autophagy	1
Post NMDA receptor activation events	1
KEAP1-NFE2L2 pathway	1
Regulation of PD-L1(CD274) Post-translational modification	1
Transmission across Chemical Synapses	1
Neuronal System	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	3
protein serine/threonine kinase activity	3
cellular anatomical structure	3
cellular response to stimulus	2
regulation of autophagy	2
macroautophagy	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
neuron projection	2
fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
lipid metabolic process	1
biosynthetic process	1
autophagy	1
positive regulation of catabolic process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
response to activity	1
cell surface receptor signaling pathway	1
positive regulation of autophagy	1
regulation of macroautophagy	1
response to nutrient levels	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
response to oxidative stress	1
cellular response to chemical stress	1

Protein interactions and networks

STRING

2380 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKAA2	PRKAB2	O43741	971
PRKAA2	PRKAB1	Q9Y478	968
PRKAA2	PRKAG1	P54619	928
PRKAA2	PRKAG2	Q9UGJ0	854
PRKAA2	PRKAG3	Q9UGI9	802
PRKAA2	PRKAA1	Q13131	748
PRKAA2	MTOR	P42345	722
PRKAA2	RPTOR	Q8N122	626
PRKAA2	PTEN	P60484	566
PRKAA2	SIRT1	Q96EB6	526
PRKAA2	ATM	Q13315	522
PRKAA2	TXNIP	Q9H3M7	498
PRKAA2	PPARGC1A	Q9UBK2	489
PRKAA2	AXIN1	O15169	485
PRKAA2	MLST8	Q9BVC4	481

IntAct

443 interactions, top by confidence:

A	B	Type	Score
PRKAA2	PRKAB2	psi-mi:“MI:0915”(physical association)	0.940
PRKAB2	PRKAA2	psi-mi:“MI:0915”(physical association)	0.940
PRKAG1	PRKAB2	psi-mi:“MI:0914”(association)	0.940
PRKAG1	PRKAA2	psi-mi:“MI:0915”(physical association)	0.930
PRKAA2	PRKAG1	psi-mi:“MI:0915”(physical association)	0.930
PRKAG3	PRKAB2	psi-mi:“MI:0914”(association)	0.800
PRKAB1	PRKAB2	psi-mi:“MI:0914”(association)	0.740
KIFC3	PRKAA2	psi-mi:“MI:0915”(physical association)	0.670
CCNB1IP1	PRKAA2	psi-mi:“MI:0915”(physical association)	0.670
ABI2	PRKAA2	psi-mi:“MI:0915”(physical association)	0.670
PRKAA2	KIFC3	psi-mi:“MI:0915”(physical association)	0.670
PRKAA2	CCNB1IP1	psi-mi:“MI:0915”(physical association)	0.670
PRKAA2	ABI2	psi-mi:“MI:0915”(physical association)	0.670
PRKAA2	MTUS2	psi-mi:“MI:0915”(physical association)	0.670
PRKAA2	REL	psi-mi:“MI:0915”(physical association)	0.670
STIM2	PRKAB2	psi-mi:“MI:0914”(association)	0.640

BioGRID (343): PRKAA2 (Affinity Capture-Western), PRKAA2 (Two-hybrid), PRKAA2 (Two-hybrid), PRKAA2 (Two-hybrid), PRKAA2 (Two-hybrid), PRKAA2 (Two-hybrid), PRKAA2 (Two-hybrid), PRKAB2 (Two-hybrid), PRKAG1 (Two-hybrid), VPS52 (Two-hybrid), TCF4 (Two-hybrid), TRIP6 (Two-hybrid), AIMP2 (Two-hybrid), ABI2 (Two-hybrid), APPBP2 (Two-hybrid)

ESM2 similar proteins: A1Z9X0, A8WUG4, A8XWC4, F1M7Y5, O13310, O19111, O74536, O97627, P00518, P07934, P09217, P13286, P23443, P26817, P26818, P26819, P31325, P34722, P35626, P41743, P54645, P54646, P67998, P67999, P83099, Q02111, Q02956, Q04759, Q05513, Q09137, Q12706, Q13131, Q16816, Q19266, Q21734, Q28948, Q2KJ16, Q3UYH7, Q5EG47, Q5R4K9

Diamond homologs: A0AUV4, A1A5Q6, A2KF29, A2XFF4, A8WYE4, B2DD29, B7XHR6, B8BBT7, C0HKC8, C0HKC9, F1QGZ6, O08678, O08679, O22932, O22971, O65554, O74536, O94168, P27448, P52497, P54645, P54646, P57059, P92958, Q00372, Q02723, Q03141, Q05512, Q09137, Q0D4B2, Q0JI49, Q13131, Q19469, Q28948, Q2QY53, Q2RAX3, Q2V452, Q38997, Q54DF2, Q54TA3

SIGNOR signaling

60 interactions.

A	Effect	B	Mechanism
metformin	up-regulates	PRKAA2
STK11	up-regulates	PRKAA2	phosphorylation
PRKAA2	up-regulates	TSC1	phosphorylation
CAMKK2	up-regulates	PRKAA2	phosphorylation
PRKAA2	“form complex”	AMPK	binding
PRKAG1	up-regulates	PRKAA2	binding
PRKAA2	down-regulates	CRTC2	phosphorylation
PRKAA2	up-regulates	TSC2	phosphorylation
PRKAA2	down-regulates	VASP	phosphorylation
PRKAA2	down-regulates	BAIAP2	phosphorylation
PRKACA	down-regulates	PRKAA2	phosphorylation
PRKAA2	up-regulates	PLD1	phosphorylation
PRKAA2	up-regulates	Gbeta	phosphorylation
PRKAA2	up-regulates	ULK1	phosphorylation
PRKAA2	down-regulates	SREBF1	phosphorylation
ULK1	down-regulates	PRKAA2	phosphorylation
ULK2	down-regulates	PRKAA2	phosphorylation
PRKAA2	up-regulates	IKBKB	phosphorylation
AICA-Ribotide	up-regulates	PRKAA2	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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
Energy dependent regulation of mTOR by LKB1-AMPK	6	43.8×	4e-07
Activation of AMPK downstream of NMDARs	5	35.2×	1e-05
MTOR signalling	6	29.5×	3e-06
Selective autophagy	5	25.8×	4e-05
Post NMDA receptor activation events	6	22.7×	1e-05
Activation of NMDA receptors and postsynaptic events	6	20.5×	1e-05
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	5	17.9×	2e-04
Regulation of TP53 Activity	7	17.2×	8e-06

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to nutrient levels	6	33.4×	1e-05
fatty acid biosynthetic process	5	20.9×	6e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	4
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2126 predictions. Top by Δscore:

Variant	Effect	Δscore
1:56645480:GAGT:G	donor_gain	1.0000
1:56645483:T:TG	donor_gain	1.0000
1:56645487:G:GG	donor_gain	1.0000
1:56674378:TAG:T	acceptor_loss	1.0000
1:56674379:A:AG	acceptor_gain	1.0000
1:56674379:AGTT:A	acceptor_gain	1.0000
1:56674380:G:GT	acceptor_gain	1.0000
1:56674380:GT:G	acceptor_gain	1.0000
1:56674380:GTT:G	acceptor_gain	1.0000
1:56674380:GTTG:G	acceptor_gain	1.0000
1:56674518:AAACT:A	donor_gain	1.0000
1:56674519:AACT:A	donor_gain	1.0000
1:56674520:ACT:A	donor_gain	1.0000
1:56674521:CT:C	donor_gain	1.0000
1:56674521:CTG:C	donor_loss	1.0000
1:56674522:TG:T	donor_loss	1.0000
1:56674523:G:C	donor_loss	1.0000
1:56674523:G:GG	donor_gain	1.0000
1:56674524:T:TC	donor_loss	1.0000
1:56674525:AA:A	donor_loss	1.0000
1:56674526:AGTAT:A	donor_loss	1.0000
1:56691380:A:AG	acceptor_gain	1.0000
1:56691384:A:AG	acceptor_gain	1.0000
1:56691387:A:AG	acceptor_gain	1.0000
1:56691388:A:G	acceptor_gain	1.0000
1:56692352:T:TA	acceptor_gain	1.0000
1:56692356:A:AG	acceptor_gain	1.0000
1:56692356:AGGT:A	acceptor_loss	1.0000
1:56692357:G:GA	acceptor_gain	1.0000
1:56692357:GGTT:G	acceptor_gain	1.0000

AlphaMissense

3653 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:56645454:G:C	G23R	1.000
1:56645455:G:A	G23D	1.000
1:56645460:G:A	G25S	1.000
1:56645460:G:C	G25R	1.000
1:56645460:G:T	G25C	1.000
1:56645461:G:A	G25D	1.000
1:56645461:G:T	G25V	1.000
1:56645466:T:A	F27I	1.000
1:56645466:T:C	F27L	1.000
1:56645466:T:G	F27V	1.000
1:56645467:T:C	F27S	1.000
1:56645467:T:G	F27C	1.000
1:56645468:C:A	F27L	1.000
1:56645468:C:G	F27L	1.000
1:56645469:G:C	G28R	1.000
1:56645470:G:A	G28D	1.000
1:56645470:G:T	G28V	1.000
1:56645475:G:A	V30M	1.000
1:56645475:G:C	V30L	1.000
1:56645475:G:T	V30L	1.000
1:56674384:G:A	G33E	1.000
1:56674414:C:A	A43E	1.000
1:56674417:T:A	V44D	1.000
1:56674419:A:C	K45Q	1.000
1:56674419:A:G	K45E	1.000
1:56674420:A:T	K45I	1.000
1:56674421:A:C	K45N	1.000
1:56674421:A:T	K45N	1.000
1:56674426:T:C	L47S	1.000
1:56674433:A:C	R49S	1.000

dbSNP variants (sampled 300 via entrez): RS1000005294 (1:56701847 T>C), RS1000013724 (1:56672861 T>C), RS1000066868 (1:56682853 T>C), RS1000110415 (1:56680020 A>C,G), RS1000116153 (1:56648299 A>G), RS1000229014 (1:56663337 C>T), RS1000310723 (1:56666314 C>G), RS1000401939 (1:56669984 G>A), RS1000459463 (1:56676860 T>G), RS1000601704 (1:56709017 T>C), RS1000816014 (1:56684061 G>C), RS1000826153 (1:56692652 T>A,C), RS1000932286 (1:56654503 C>T), RS1001034561 (1:56652372 G>A,C,T), RS1001061114 (1:56643846 T>G)

Disease associations

OMIM: gene MIM:600497 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001389_1	Lymphocyte count	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (9): CHEMBL2096907 (PROTEIN COMPLEX GROUP), CHEMBL2116 (SINGLE PROTEIN), CHEMBL3038454 (PROTEIN COMPLEX), CHEMBL3038455 (PROTEIN COMPLEX), CHEMBL3038456 (PROTEIN COMPLEX), CHEMBL3038457 (PROTEIN COMPLEX), CHEMBL3885504 (PROTEIN COMPLEX), CHEMBL4106158 (PROTEIN COMPLEX), CHEMBL4106159 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 429,223 (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
CHEMBL752	ADENOSINE PHOSPHATE	4	165,316
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL295124	BERBERINE	4	26,682
CHEMBL305660	EBASTINE	4	10,024
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL165	RESVERATROL	3	60,144
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL473659	GINSENOSIDE RD	3	1,735
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL273453	ALDOSTERONE	2	50,544
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL575448	BMS-754807	2	406
CHEMBL1908397	KW-2449	1	622

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
PRKAA2 T172 PHOSPHORYLATION	ACLY SiRNA	Cancer	Sensitivity/Response	CIViC E	EID913

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10789038	PRKAA2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — AMPK subfamily

Binding affinities (BindingDB)

203 measured of 648 human assays (648 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[2-[1-[(5-ethoxypyrazin-2-yl)methyl]piperidin-4-yl]indazol-5-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	0.86 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
2-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-1H-1,2,4-triazol-5-one	EC50	1 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(4-morpholin-2-ylphenyl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	1 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
2-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-1H-pyrazol-5-one	EC50	1 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
Staurosporine	KD	1.7 nM
[2-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]indazol-5-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	1.8 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
4-[[4-[6-[1-[(5-ethoxypyrazin-2-yl)methyl]piperidin-4-yl]-1-methylindole-2-carbonyl]piperazin-1-yl]methyl]benzonitrile	EC50	1.8 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
2-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-2-methylpropane-1,3-diol	EC50	2 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
1-[1-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]triazol-4-yl]-2,2,2-trifluoroethane-1,1-diol	EC50	2 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
2-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-1H-pyrimidin-6-one	EC50	2 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(tetrazol-2-ylmethyl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	2 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
4-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]pyrrolidin-2-one	EC50	2 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[2-(dimethylamino)ethoxy]phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	2 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(2R,3S,5R)-5-[[4,6-difluoro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	2 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
4-[4-[4,6-difluoro-2-[(3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-1H-benzimidazol-5-yl]phenyl]-N-methylbenzamide	EC50	2 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
4-[[4-[5-[1-[(5-ethoxypyrazin-2-yl)methyl]piperidin-4-yl]-1-methylindole-2-carbonyl]piperazin-1-yl]methyl]benzonitrile	EC50	2.8 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	3 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	3 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
4-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-6-methyl-4H-pyridazin-3-one	EC50	3 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
[6-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]-1-methylbenzimidazol-2-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	3 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
2-[4-[4-[4,6-difluoro-2-[(3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-1H-benzimidazol-5-yl]phenyl]phenyl]-1H-pyrimidin-6-one	EC50	3 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
(2R,3S,5R)-5-[[4,6-difluoro-5-[4-(4-morpholin-2-ylphenyl)phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	3 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
4-[[4-[5-[1-[(5-methoxypyrazin-2-yl)methyl]piperidin-4-yl]-1-methylindole-2-carbonyl]piperazin-1-yl]methyl]benzonitrile	EC50	3.3 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
[6-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]imidazo[1,2-a]pyridin-2-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	3.6 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
3-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-1H-imidazol-2-one	EC50	4 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
4-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]butanoic acid	EC50	4 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[5-[4-[4-(2-amino-3-methylimidazol-4-yl)phenyl]phenyl]-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	4 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
3-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-1,2,4-oxadiazolidin-5-one	EC50	4 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(hydroxymethyl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	4 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(imidazol-1-ylmethyl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	4 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
3-[4-[4-[4,6-difluoro-2-[(3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-1H-benzimidazol-5-yl]phenyl]phenyl]pyrrolidin-2-one	EC50	4 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]-3-fluorobenzonitrile	EC50	5 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(diethylamino)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	5 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(2R,3S,5R)-5-[[5-[4-[4-(3,5-diamino-1,2,4-triazol-1-yl)phenyl]phenyl]-4,6-difluoro-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	5 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
[7-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]imidazo[1,2-a]pyridin-2-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	5.1 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
[5-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]-1-methylpyrrolo[2,3-c]pyridin-2-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	5.2 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
2-[[(3R,3aR,6R,6aR)-3-prop-2-enoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridine	EC50	6 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
5-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]-3,4-dihydro-2H-pyrrole-2-carboxylic acid	EC50	6 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
2-[4-[4-[6-chloro-2-[(3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-1H-benzimidazol-5-yl]phenyl]phenyl]-2-methylpropane-1,3-diol	EC50	6 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
[5-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	6.5 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
2-[4-[4-[6-chloro-2-[(3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-1H-benzimidazol-5-yl]phenyl]phenyl]-1H-pyrimidin-6-one	EC50	7 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
(2R,3S,5R)-5-[[6-chloro-5-[4-[4-(3,5-diamino-1,2,4-triazol-1-yl)phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	7 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
5-[4-[4-[4,6-difluoro-2-[(3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-1H-benzimidazol-5-yl]phenyl]phenyl]-3H-1,3,4-oxadiazol-2-one	EC50	7 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
(2R,3S,5R)-5-[[4,6-difluoro-5-[4-[4-[4-(2-hydroxy-2-methylpropyl)pyrazol-1-yl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	7 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(3-methyloxetan-3-yl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	8 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives
(2R,3S,5R)-5-[[4,6-difluoro-5-[4-(4-piperidin-4-ylsulfonylphenyl)phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	8 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
[6-[1-[(5-methoxypyrazin-2-yl)methyl]piperidin-4-yl]-1H-benzimidazol-2-yl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone	EC50	8.3 nM	US-9428501: Bicyclic nitrogen-containing aromatic heterocyclic amide compound
(2R,3S,5R)-5-[[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	9 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
(2R,3S,5R)-5-[[4,6-difluoro-5-[4-[4-(2H-tetrazol-5-yl)phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	EC50	9 nM	US-9527839: Benzimidazole tetrahydropyran derivatives
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-(2-piperidin-4-ylethynyl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	10 nM	US-9290517: Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives

ChEMBL bioactivities

696 potent at pChembl≥5 of 751 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	EC50	0.5	nM	CHEMBL3986249
9.15	EC50	0.7	nM	CHEMBL3979403
9.07	EC50	0.86	nM	CHEMBL3969654
9.00	EC50	1	nM	CHEMBL4108031
9.00	EC50	1	nM	CHEMBL4111083
9.00	EC50	1	nM	CHEMBL4110796
9.00	EC50	1	nM	CHEMBL4167177
9.00	EC50	1	nM	CHEMBL5179319
9.00	EC50	1	nM	CHEMBL5181529
9.00	EC50	1	nM	CHEMBL5183763
9.00	IC50	1	nM	CHEMBL5183579
8.89	EC50	1.3	nM	ALDOSTERONE
8.77	EC50	1.7	nM	CHEMBL3975011
8.74	EC50	1.8	nM	CHEMBL3923669
8.74	EC50	1.8	nM	CHEMBL3970694
8.74	EC50	1.8	nM	CHEMBL3955171
8.70	EC50	2	nM	CHEMBL3957286
8.70	EC50	2	nM	CHEMBL4109999
8.70	EC50	2	nM	CHEMBL4108071
8.70	EC50	2	nM	CHEMBL4114120
8.70	EC50	2	nM	CHEMBL4115027
8.70	EC50	2	nM	CHEMBL4113251
8.70	EC50	2	nM	CHEMBL4115276
8.70	EC50	2	nM	CHEMBL4111692
8.70	EC50	2	nM	CHEMBL3393127
8.70	EC50	2	nM	CHEMBL5194054
8.70	EC50	2	nM	CHEMBL5180431
8.64	EC50	2.3	nM	CHEMBL3953722
8.62	EC50	2.4	nM	CHEMBL3893781
8.59	EC50	2.602	nM	CHEMBL3970868
8.55	EC50	2.8	nM	CHEMBL3895006
8.55	IC50	2.82	nM	CHEMBL3393137
8.54	EC50	2.9	nM	CHEMBL4107500
8.52	EC50	3	nM	CHEMBL4114943
8.52	EC50	3	nM	CHEMBL4112741
8.52	EC50	3	nM	CHEMBL4114853
8.52	EC50	3	nM	CHEMBL3955631
8.52	EC50	3	nM	CHEMBL3393128
8.52	EC50	3	nM	CHEMBL5174868
8.52	EC50	3	nM	CHEMBL5828708
8.48	EC50	3.3	nM	CHEMBL3983813
8.44	EC50	3.6	nM	CHEMBL3904401
8.40	EC50	4	nM	CHEMBL3957286
8.40	EC50	4	nM	CHEMBL4115644
8.40	EC50	4	nM	CHEMBL4107245
8.40	EC50	4	nM	CHEMBL4115405
8.40	EC50	4	nM	CHEMBL4110254
8.40	EC50	4	nM	CHEMBL4112726
8.40	EC50	4	nM	CHEMBL4112959
8.40	EC50	4	nM	CHEMBL5203262

PubChem BioAssay actives

275 with measured affinity, of 1802 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
[6-chloro-2-hydroxy-5-(1-methylindol-5-yl)-1H-indol-3-yl]-(3-methoxy-1,2-oxazol-5-yl)methanone	1320676: Activation of recombinant human His-tagged AMPK alpha2 (2 to 552 residues)/beta1 (2 to 270 residues)/gamma2 (2 to 569 residues) expressed in baculovirus infected sf21 cells preincubated for 30 mins followed by biotinylated ACC-CREBp peptide substrate addition measured after 45 mins by HTRF assay	ec50	0.0007	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[(4-fluorophenyl)methyl]piperazine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0010	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[fluoro-(4-fluorophenyl)methyl]piperidine-1-carbonyl]pyridine-2-carboxamide	1855899: Activation of AMPK in human HepG2 cells assessed as reduction in mitochondrial ATP production incubated for 1 hr	ic50	0.0010	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[(4-fluorophenyl)methyl]-3,3-dimethylpiperazine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0010	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[(4-methoxyphenyl)methyl]piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0010	uM
(3R,3aR,6R,6aR)-6-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	1552802: Activation of recombinant human AMPK expressed in Sf9 cells using SAMS peptide as substrate preincubated for 30 mins followed by substrate addition and measured after 60 mins by fluorescence based assay	ec50	0.0010	uM
(8S,9S,10R,11S,13R,14S,17S)-11-hydroxy-17-(2-hydroxyacetyl)-10-methyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthrene-13-carbaldehyde	2074041: Agonist activity at AMPK (unknown origin)	ec50	0.0013	uM
2-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]benzene-1,3-diol	1320700: Activation of human recombinant AMPK alpha2/beta2/gamma1 expressed in African green monkey COS7 cells assessed as increase in biotinylated AAC (1 to 120 residues) peptide phosphorylation at Ser-79 residue measured after 60 mins by Alphascreen assay	ec50	0.0020	uM
5-[[6-chloro-5-(1-methylindol-5-yl)-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1471575: Agonist activity at human recombinant phosphorylated AMPK complex 7 alpha2/beta1/gamma1 expressed in baculovirus infected Sf21 cells assessed as phosphorylation of 5-FAM-labeled SAMS substrate preincubated for 30 mins in presence of AMPK activator followed by substrate addition measured after 60 mins	ec50	0.0020	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-fluoro-4-(4-fluorobenzoyl)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0020	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(4-fluorobenzoyl)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0020	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-6-[4-(4-methoxybenzoyl)piperidine-1-carbonyl]pyridine-3-carboxamide	1855899: Activation of AMPK in human HepG2 cells assessed as reduction in mitochondrial ATP production incubated for 1 hr	ic50	0.0028	uM
5-[[6-chloro-5-[4-(2-hydroxyphenyl)phenyl]-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1471575: Agonist activity at human recombinant phosphorylated AMPK complex 7 alpha2/beta1/gamma1 expressed in baculovirus infected Sf21 cells assessed as phosphorylation of 5-FAM-labeled SAMS substrate preincubated for 30 mins in presence of AMPK activator followed by substrate addition measured after 60 mins	ec50	0.0030	uM
5-[4-(4-cyanophenoxy)piperidine-1-carbonyl]-N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0030	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(2,4-difluorophenoxy)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0040	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625047: Binding constant for AMPK-alpha2 kinase domain	kd	0.0041	uM
N-[4-[[(2-hydroxy-1H-indol-3-yl)-phenylmethylidene]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide	1474638: Inhibition of AMPK (unknown origin) using SAMS peptide as substrate measured after 30 mins in presence of [gamma32P]ATP by liquid scintillation counting method	ki	0.0042	uM
[4-[5-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]-1,3,4-oxadiazol-2-yl]phenyl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone;bis(4-methylbenzenesulfonic acid)	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0045	uM
4-[(4-methoxyphenyl)methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperazine-1-carboxamide	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0047	uM
2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-5-carboxylic acid	1474638: Inhibition of AMPK (unknown origin) using SAMS peptide as substrate measured after 30 mins in presence of [gamma32P]ATP by liquid scintillation counting method	ki	0.0049	uM
5-[4-(4-cyanobenzoyl)piperidine-1-carbonyl]-N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0050	uM
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]-3-fluorobenzonitrile	1320688: Activation of full length human recombinant AMPK alpha2/beta1/gamma1 expressed in baculovirus infected sf21 cells using 5’-FAM-SAMS peptide substrate after 45 mins by fluorescence assay	ec50	0.0050	uM
4,6-difluoro-5-[4-[(2S)-oxan-2-yl]phenyl]-1H-indole-3-carboxylic acid	1398173: Activation of full-length recombinant N-terminal His-tagged human AMPKalpha2beta1gamma1 expressed in Escherichia coli BL21 cells using Cy-5 SAMS peptide as substrate preincubated for 60 mins followed by substrate addition and measured after 60 mins in presence of PP2a by TR-FRET assay	ec50	0.0060	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[2-(4-fluorophenyl)propan-2-yl]piperazine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0060	uM
bis(N-cyclohexylcyclohexanamine);[5-(5-oxo-2H-1,2-oxazol-3-yl)furan-2-yl]phosphonic acid	580978: Activation of human AMPK after 15 mins	ec50	0.0063	uM
6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid	1315840: Activation of recombinant human AMPK alpha2/beta1/gamma1 using Cy5-labelled SAMS as substrate assessed as protection from Thr172 residue dephosphorylation preincubated for 15 mins followed by incubation with PP2a for 60 mins measured 60 mins post okadaic acid/Cy5-labelled SAMS and ATP addition by TR-FRET assay	ec50	0.0068	uM
5-[[5-chloro-6-(2-phenylethynyl)-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1471575: Agonist activity at human recombinant phosphorylated AMPK complex 7 alpha2/beta1/gamma1 expressed in baculovirus infected Sf21 cells assessed as phosphorylation of 5-FAM-labeled SAMS substrate preincubated for 30 mins in presence of AMPK activator followed by substrate addition measured after 60 mins	ec50	0.0070	uM
4-[[4-(trifluoromethyl)phenyl]methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperazine-1-carboxamide	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0079	uM
5-[[6-chloro-5-(4-phenylphenyl)-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1471575: Agonist activity at human recombinant phosphorylated AMPK complex 7 alpha2/beta1/gamma1 expressed in baculovirus infected Sf21 cells assessed as phosphorylation of 5-FAM-labeled SAMS substrate preincubated for 30 mins in presence of AMPK activator followed by substrate addition measured after 60 mins	ec50	0.0080	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(2,4-difluorobenzoyl)piperidine-1-carbonyl]pyridine-2-carboxamide	1855899: Activation of AMPK in human HepG2 cells assessed as reduction in mitochondrial ATP production incubated for 1 hr	ic50	0.0080	uM
6-[4-(4-methoxybenzoyl)piperidine-1-carbonyl]-N-[1-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-4-yl]pyridine-3-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0090	uM
6-[4-(4-pyrrolidin-1-ylbenzoyl)piperidine-1-carbonyl]-N-[1-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-4-yl]pyridine-3-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0090	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-5-carboxylate	1474638: Inhibition of AMPK (unknown origin) using SAMS peptide as substrate measured after 30 mins in presence of [gamma32P]ATP by liquid scintillation counting method	ki	0.0092	uM
7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-[3-(pyrrolidin-1-ylmethyl)anilino]pyrrolo[2,3-d]pyrimidin-6-one	1992921: Inhibition of AMPKalpha1/2 (unknown origin)	ic50	0.0100	uM
1-[(4-methoxyphenyl)methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperidine-4-carboxamide;dihydrochloride	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0110	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(4-methoxyphenoxy)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0110	uM
5-[[6-chloro-5-[4-(1H-pyrazol-5-yl)phenyl]-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1471575: Agonist activity at human recombinant phosphorylated AMPK complex 7 alpha2/beta1/gamma1 expressed in baculovirus infected Sf21 cells assessed as phosphorylation of 5-FAM-labeled SAMS substrate preincubated for 30 mins in presence of AMPK activator followed by substrate addition measured after 60 mins	ec50	0.0110	uM
1-[(6-methoxy-3-pyridinyl)methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperidine-4-carboxamide	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0120	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	435149: Binding constant for AMPK-alpha2 kinase domain	kd	0.0120	uM
N-[1-[(4-fluorophenyl)methyl]piperidin-4-yl]-6-[4-(4-pyrrolidin-1-ylbenzoyl)piperidine-1-carbonyl]pyridine-3-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0120	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-6-[4-(2,4-difluorophenoxy)piperidine-1-carbonyl]pyridine-3-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0130	uM
5-[4-[(4-cyanophenyl)methyl]piperidine-1-carbonyl]-N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0140	uM
N-methyl-3-(3,12,13,23-tetrazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2,4,6,8,10,14,17,19,21-decaen-23-yl)propan-1-amine;dihydrochloride	2075599: Inhibition of human AMPK using HMRSAMSGLHLVKRR as substrate in presence of ATP	ic50	0.0144	uM
2-chloro-5-[[5-chloro-6-(2-phenylethynyl)-1H-benzimidazol-2-yl]oxy]benzoic acid	1471575: Agonist activity at human recombinant phosphorylated AMPK complex 7 alpha2/beta1/gamma1 expressed in baculovirus infected Sf21 cells assessed as phosphorylation of 5-FAM-labeled SAMS substrate preincubated for 30 mins in presence of AMPK activator followed by substrate addition measured after 60 mins	ec50	0.0150	uM
2-[[5-[1-[(4-fluorophenyl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-6-methyl-2-pyridinyl]oxymethyl]-3,5-dimethyl-1H-pyridin-4-one	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0160	uM
5-(4-benzylpiperazine-1-carbonyl)-N-(1-benzylpiperidin-4-yl)pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0160	uM
5-[(Z)-(5-cyano-2-oxo-1H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	1737705: Inhibition of recombinant human His6-tagged AMPK alpha2 using ULight CRBtide as substrate incubated for 1 hr followed by substrate addition and measured after 1 hr by TR-FRET assay	ic50	0.0162	uM
3-[[(2R,3S,4S,5R,6S)-6-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-[[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-12-hydroxy-4,4,8,10,14-pentamethyl-17-[(2S)-6-methyl-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]oxan-3-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methoxy]-3-oxopropanoic acid	1364697: Activation of recombinant AMPKalpha2beta1gamma1 (unknown origin) expressed in Escherichia coli BL21 in presence of CaMKKbeta (unknown origin) incubated for 45 mins in presence of substrate-1 peptide and ATP by HTRF assay	ec50	0.0168	uM
3-[[(2R,3S,4S,5R,6S)-6-[(2R,3R,4S,5S,6R)-2-[[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-17-[(2S)-2-[(2S,3R,4S,5S,6R)-6-[[(2R,3R,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxymethyl]-3,4,5-trihydroxyoxan-2-yl]oxy-6-methylhept-5-en-2-yl]-12-hydroxy-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methoxy]-3-oxopropanoic acid	1364697: Activation of recombinant AMPKalpha2beta1gamma1 (unknown origin) expressed in Escherichia coli BL21 in presence of CaMKKbeta (unknown origin) incubated for 45 mins in presence of substrate-1 peptide and ATP by HTRF assay	ec50	0.0168	uM
(2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-[[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-12-hydroxy-4,4,8,10,14-pentamethyl-17-[(2S)-6-methyl-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol	1364697: Activation of recombinant AMPKalpha2beta1gamma1 (unknown origin) expressed in Escherichia coli BL21 in presence of CaMKKbeta (unknown origin) incubated for 45 mins in presence of substrate-1 peptide and ATP by HTRF assay	ec50	0.0168	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
dorsomorphin	increases phosphorylation, affects cotreatment, decreases expression, decreases reaction, increases expression (+1 more)	4
Resveratrol	increases abundance, increases reaction, decreases phosphorylation, decreases abundance, increases expression (+4 more)	4
sodium arsenite	decreases expression, increases expression	3
AICA ribonucleotide	increases activity, increases phosphorylation, affects reaction, increases expression	3
Metformin	affects reaction, decreases phosphorylation, decreases reaction, increases activity, increases phosphorylation	3
nuciferine	decreases phosphorylation, decreases reaction, affects reaction, decreases expression, increases phosphorylation	2
6,8-diallyl 5,7-dihydroxy 2-(2-allyl 3-hydroxy 4-methoxyphenyl)1-H benzo(b)pyran-4-one	increases reaction, increases activity, increases phosphorylation, decreases reaction	2
Doxorubicin	increases expression, decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
Palmitic Acid	affects cotreatment, affects expression, decreases phosphorylation, decreases reaction	2
Particulate Matter	increases phosphorylation, affects response to substance, affects expression, decreases expression, affects reaction (+1 more)	2
aristolochic acid I	decreases expression	1
geldanamycin	decreases expression, decreases phosphorylation, decreases reaction	1
tempol	affects expression, decreases reaction	1
taxifolin	decreases phosphorylation	1
testosterone enanthate	affects expression	1
bisphenol A	increases phosphorylation	1
gramine	increases phosphorylation	1
acadesine	increases expression, increases reaction	1
trichostatin A	increases expression	1
sulforaphane	increases phosphorylation, increases reaction	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression	1
syringin	decreases phosphorylation	1
2-chloroethyl ethyl sulfide	decreases reaction, decreases phosphorylation, increases degradation, decreases expression	1
schizandrin A	decreases phosphorylation	1
bafilomycin A1	decreases expression, decreases reaction	1

ChEMBL screening assays

549 unique, capped per target: 548 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1053698	Binding	Induction of AMPK phosphorylation in human HepG2 cells by Western blot analysis in presence of 33 mM glucose	Palbinone and triterpenes from Moutan Cortex (Paeonia suffruticosa, Paeoniaceae) stimulate glucose uptake and glycogen synthesis via activation of AMPK in insulin-resistant human HepG2 Cells. — Bioorg Med Chem Lett
CHEMBL4649950	Functional	AMP-dependent Kinase enzyme assay. An in vitro enzyme assay that detects ADP turnover that is directly proportional to AMPK activity. This uses naive AMPK that is activated during the assay with MK-8722	University of Dundee, Small-Polar-MMV Screening Library

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8N2	Abcam HCT 116 PRKAA2 KO	Cancer cell line	Male
CVCL_B9AN	Abcam MCF-7 PRKAA2 KO	Cancer cell line	Female
CVCL_B9QB	Abcam A-549 PRKAA2 KO	Cancer cell line	Male
CVCL_D7YA	Ubigene A-549 PRKAA2 KO	Cancer cell line	Male
CVCL_D8TR	Ubigene HCT 116 PRKAA2 KO	Cancer cell line	Male
CVCL_D9PD	Ubigene HEK293 PRKAA2 KO	Transformed cell line	Female
CVCL_E0LP	Ubigene HeLa PRKAA2 KO	Cancer cell line	Female
CVCL_TG62	HAP1 PRKAA2 (-) 1	Cancer cell line	Male
CVCL_TG63	HAP1 PRKAA2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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