Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTLAFZV)

• DTT Name: AMP-activated protein kinase (AMPK)
• Synonyms: AMPK; 5'-AMP-activated protein kinase
• Gene Name: PRKAA1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: AAPK1_HUMAN ; AAKB1_HUMAN ; AAKG1_HUMAN
• TTD ID: T38875
• Sequence:
  MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNR
  QKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNG
  RLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEF
  LRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDG
  IFYTPQYLNPSVISLLKHMLQVDPMKRATIKDIREHEWFKQDLPKYLFPEDPSYSSTMID
  DEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLATSPPDS
  FLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRPNDI
  MAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDFRSIDDE
  ITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPRPG
  SHTIEFFEMCANLIKILAQ
• 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.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  Regulation of autophagy (hsa04140)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Circadian rhythm (hsa04710)
  Insulin signaling pathway (hsa04910)
  Adipocytokine signaling pathway (hsa04920)
  Oxytocin signaling pathway (hsa04921)
  Glucagon signaling pathway (hsa04922)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Hypertrophic cardiomyopathy (HCM) (hsa05410)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  Activation of PPARGC1A (PGC-1alpha) by phosphorylation (R-HSA-2151209)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Translocation of GLUT4 to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DTT

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acadesine	DM1RMF5	Diabetic complication	5A2Y	Phase 3	[1]
ENERGI-F701	DMMIHSO	Alopecia	ED70	Phase 2	[2]
Imeglimin	DMMQFG2	Diabetic complication	5A2Y	Phase 2	[3]
MB-11055	DM3RBJW	Fatty liver disease	DB92.Z	Phase 2	[4]
O-304	DMXM34I	Type 2 diabetes	5A11	Phase 2	[5]
PXL-770	DMNSRY7	Non-alcoholic fatty liver disease	DB92	Phase 2	[6]
IM156	DM4MY9C	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Phenformin	DMQ52JG	Diabetic complication	5A2Y	Withdrawn from market	[8]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[9]
4-(3-bromopyrazolo[1,5-a]pyrimidin-6-yl)phenol	DML5NF6	Discovery agent	N.A.	Investigative	[10]
Debio-0930	DMFTNAP	Metabolic disorder	5C50-5D2Z	Investigative	[11]
Dorsomorphin	DMKYXJW	Discovery agent	N.A.	Investigative	[10]
OSU-53	DMQPJXT	Triple negative breast cancer	2C60-2C65	Investigative	[12]
PMID23639540C13a	DMLXOAQ	Discovery agent	N.A.	Investigative	[13]
SU 6656	DMF1P6W	Discovery agent	N.A.	Investigative	[14]
TG-1022	DMSG0TL	Obesity	5B81	Investigative	[11]

References

• [1] Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin Pharmacother. 2008 Aug;9(12):2137-44.
• [2] Clinical pipeline report, company report or official report of Energenesis Biomedical.
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032542)
• [4] Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase.Mol Pharmacol.2007 Jul;72(1):62-72.
• [5] Clinical pipeline report, company report or official report of Betagenon.
• [6] Clinical pipeline report, company report or official report of Poxel SA.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem J. 2008 Jan 15;409(2):449-59.
• [9] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [10] 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.
• [11] 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. (Target id: 1540).
• [12] A novel dual AMPK activator/mTOR inhibitor inhibits thyroid cancer cell growth. J Clin Endocrinol Metab. 2015 May;100(5):E748-56.
• [13] 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.
• [14] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.