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AMP-activated protein kinase: the current landscape for drug development

Abstract

Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elicit beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (201709FDN-CEBA-116200 to G.R.S.), Diabetes Canada (DI-5-17-5302-GS) and the Medical Research Council UK (grant MC-A654-5QB10 to D.C.). G.R.S. is supported by a Canada Research Chair and a J. Bruce Duncan Chair in Metabolic Diseases.

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Competing interests

G.R.S. has received research funding from Esperion Therapeutics and Rigel Pharmaceuticals, reagents from Pfizer and Merck, and honoraria and/or consulting fees from Astra Zeneca, Eli-Lilly, Esperion Therapeutics, Novo Nordisk, Poxel, Pfizer, Merck, Rigel and Terns.

Correspondence to Gregory R. Steinberg.

Glossary

Cardiovascular disease

(CVD). A term encompassing diseases affecting the heart or circulatory system.

Non-alcoholic fatty liver disease

(NAFLD). A very common disease in humans in which there is an excessive accumulation of fat in the liver (steatosis) in individuals who are not alcoholic.

Cystathionine-β-synthase (CBS) domains

Small protein domains (typically ~60 amino acids) that usually occur as tandem repeats, sometimes referred to as a Bateman domain, and that often bind to nucleotide or nucleotide-like molecules. AMP-activated protein kinase γ subunits contain four CBS domains, three of which bind adenine nucleotides.

Autophagy

A process by which organisms degrade organelles and macromolecules including proteins and recycle nutrients in response to starvation.

Lipogenesis

A metabolic pathway for the synthesis of fatty acids and triglycerides.

Mitophagy

Similar to autophagy, but refers specifically to the process by which cells turnover mitochondria.

Allosteric activator

A molecule that activates an enzyme by binding at a site distinct from the active site.

Gluconeogenesis

A metabolic pathway for the synthesis of glucose from precursor substrates such as lactate and amino acids.

Non-alcoholic steatohepatitis

(NASH). A severe form of non-alcoholic fatty liver disease in which the liver becomes inflamed.

Thermogenesis

A process by which cells generate heat.

Atherosclerosis

The formation of solid plaques within arteries that block normal blood flow.

Wolff–Parkinson–White syndrome

An electrical conductance abnormality that leads to increased heart rate (tachycardia); mutations in AMP-activated protein kinase γ2 are often associated with this syndrome.

Nociceptors

Neurons that respond to damaging stimuli and transmit a response to the brain that is perceived as pain.

Pharmacokinetics

How an organism processes a drug.

Pharmacodynamics

How drugs affect an organism.

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Fig. 1: Physiological and pharmacological AMPK regulation.
Fig. 2: Proteins and pathways regulated by AMPK.
Fig. 3: Tissue-specific roles of AMPK in the metabolic syndrome.