ArticleThe Biochemical journal2022
Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator.
Article in The Biochemical journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- The pan-AMPK activator MK-8722 outperforms the AMPK activators SC4 and A-769662 in human endothelial cells.Bioscience reports · 2026Article
- Small Molecule Insulin Sensitisers: New Leads and Targets for Next-Generation Insulin Sensitising Strategies.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- AMPK Therapy-A Little Goes A Long Way.Cells · 2026Review
- Hypoxia-inducible factors: Regulatory functions and status as a therapeutic target in gastric cancer (Review).Oncology letters · 2026Review
- Review
- AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.Nature metabolism · 2026Review
- The role of AMPK signaling pathway in the pathogenesis of type 2 diabetes mellitus with its complications and related metabolic disorders.Metabolism open · 2025Review
- The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.Annual review of cell and developmental biology · 2025Review
- Article
- Discovery of novel potential 11β-HSD1 inhibitors through combining deep learning, molecular modeling, and bio-evaluation.Molecular diversity · 2025Article
- AMPK phosphosite profiling by label-free mass spectrometry reveals a multitude of mTORC1-regulated substrates.npj metabolic health and disease · 2025Article
- Reversal of metformin's anti-proliferative effect in fission yeastnpj metabolic health and disease · 2025Article
- Mitochondrial bioenergetics dysfunction in T2DM: linking oxidative stress to insulin resistance.Frontiers in endocrinology · 2025Review
- The metabolic sensor AMPK: Twelve enzymes in one.Molecular metabolism · 2024Review
- PAK4 phosphorylates and inhibits AMPKα to control glucose uptake.Nature communications · 2024Article
- Structural and molecular dynamics simulation studies of CBL-interacting protein kinase CIPK and its complexes related to plant salinity stress.Journal of molecular modeling · 2024Article
- Genome-wide screens connect HD82 loss-of-function to purine analog resistance in African trypanosomes.mSphere · 2024Article
- HIF in Gastric Cancer: Regulation and Therapeutic Target.Molecules (Basel, Switzerland) · 2022Review
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Authors and funding
21 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes. Substitution of the LHS 2-hydroxyphenyl group with polar-substituted cyclohexene-based probes resulted in two AMPK agonists, MSG010 and MSG011, which did not display α2-selectivity when screened against a panel of AMPK complexes. By radiolabel kinase assay, MSG010 and MSG011 activated α2β2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2β1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and α2-Lys31 for directing α2-selectivity. MSG011 induced robust AMPK signalling in mouse primary hepatocytes and commonly used cell lines, and in most cases this occurred in the absence of changes in phosphorylation of the kinase activation loop residue α-Thr172, a classical marker of AMP-induced AMPK activity. These findings will guide future design of α2β2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body.
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