Target Information

Target General Information

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Target ID

T38875 (Former ID: TTDS00209)

Target Name

AMP-activated protein kinase (AMPK)

Synonyms

AMPK; 5'-AMP-activated protein kinase

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Gene Name

PRKAA1; PRKAB1; PRKAG1

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Acute diabete complication [ICD-11: 5A2Y]

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. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. 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. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. 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 TSC2, RPTOR 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. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. 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 has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.

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BioChemical Class

Kinase

UniProt ID

AAPK1_HUMAN ; AAKB1_HUMAN ; AAKG1_HUMAN

Sequence

MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNR
QKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNG
RLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEF
LRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDG
IFYTPQYLNPSVISLLKHMLQVDPMKRATIKDIREHEWFKQDLPKYLFPEDPSYSSTMID
DEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLATSPPDS
FLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRPNDI
MAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDFRSIDDE
ITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPRPG
SHTIEFFEMCANLIKILAQ

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HIT2.0 ID

T81I4T

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

Acadesine

Drug Info

Phase 3

Diabetic complication

[1], [2]

Imeglimin

Drug Info

Phase 2

Type-2 diabetes

[6], [7]

MB-11055

Drug Info

Phase 2

Fatty liver disease

[8]

IM156

Drug Info

Phase 1

Solid tumour/cancer

[9]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

Phenformin

Drug Info

Withdrawn from market

Diabetic complication

[10]

Mode of Action

[+] 4 Modes of Action

Modulator

[+] 3 Modulator drugs

Acadesine

Drug Info

[1]

Imeglimin

Drug Info

[11]

MB-11055

Drug Info

[12]

Inhibitor

[+] 5 Inhibitor drugs

IM156

Drug Info

[9]

4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole

Drug Info

[16]

4-(3-bromopyrazolo[1,5-a]pyrimidin-6-yl)phenol

Drug Info

[17]

PMID23639540C13a

Drug Info

[19]

SU 6656

Drug Info

[20]

Activator

[+] 1 Activator drugs

Phenformin

Drug Info

[13], [14], [15]

Stimulator

[+] 2 Stimulator drugs

Debio-0930

Drug Info

[18]

TG-1022

Drug Info

[18]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 12 KEGG Pathways	+
1	FoxO signaling pathway
2	Regulation of autophagy
3	mTOR signaling pathway
4	PI3K-Akt signaling pathway
5	AMPK signaling pathway
6	Circadian rhythm
7	Insulin signaling pathway
8	Adipocytokine signaling pathway
9	Oxytocin signaling pathway
10	Glucagon signaling pathway
11	Non-alcoholic fatty liver disease (NAFLD)
12	Hypertrophic cardiomyopathy (HCM)
Reactome	[+] 4 Reactome Pathways	+
1	Translocation of GLUT4 to the plasma membrane
2	Macroautophagy
3	Activation of PPARGC1A (PGC-1alpha) by phosphorylation
4	TP53 Regulates Metabolic Genes
WikiPathways	[+] 10 WikiPathways	+
1	Insulin Signaling
2	Energy dependent regulation of mTOR by LKB1-AMPK
3	JAK/STAT
4	BDNF signaling pathway
5	Leptin signaling pathway
6	SREBF and miR33 in cholesterol and lipid homeostasis
7	SREBP signalling
8	Signaling by Insulin receptor
9	TOR Signaling
10	AMPK Signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin Pharmacother. 2008 Aug;9(12):2137-44.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5133).

REF 3

Clinical pipeline report, company report or official report of Betagenon.

REF 4

ClinicalTrials.gov (NCT03763877) A Study of the Efficacy and Safety of PXL770 Versus Placebo After 12 Weeks of Treatment in Patients With NAFLD. U.S. National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT03351322) ENERGI-F701 for Female Hair Loss Treatment. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT01951235) A Study of the Efficacy and Safety of 4 Doses of Imeglimin After 24 Weeks of Treatment in Subjects With Type 2 Diabetes. U.S. National Institutes of Health.

REF 7

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800035046)

REF 9

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 10

Drug information of Phenformin, 2008. eduDrugs.

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032542)

REF 12

Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase.Mol Pharmacol.2007 Jul;72(1):62-72.

REF 13

Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem J. 2008 Jan 15;409(2):449-59.

REF 14

Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. Genome Res. 2000 Oct;10(10):1546-60.

REF 15

Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 1996 Jan 12;271(2):611-4.

REF 16

Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.

REF 17

The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular a... Bioorg Med Chem Lett. 2010 Nov 15;20(22):6394-9.

REF 18

REF 19

Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3248-52.

REF 20

The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.

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