Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator

• DOI: 10.1042/bcj20220067
• Publication Date: 2022-05-13T10:03:24Z
• Authors: Ashley J. Ovens; Yi Sing Gee; Naomi X.Y. Ling; Dingyi Yu; Justin P. Hardee; Jin D. Chung; Kevin R.W. Ngoei; Nicholas J. Waters; Nolan J. Hoffman; John W. Scott; Kim Loh; Katrin Spengler; Regine Heller; Michael W. Parker; Gordon S. Lynch; Fei Huang; Sandra Galic; Bruce E. Kemp; Jonathan B. Baell; Jonathan S. Oakhill; Christopher G. La...
• Keywords: AMP-Activated Protein Kinase

The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake provides an opportunity for new strategies to treat type 2 diabetes insulin resistance, recent genetic pharmacological studies indicating the α2β2γ1 isoform combination as complex primarily responsible. With goal developing α2β2-specific activators, here we perform structure/function analysis 2-hydroxybiphenyl group SC4, activator tendency α2-selectivity that also capable potently activating β2 complexes. Substitution LHS 2-hydroxyphenyl polar-substituted cyclohexene-based probes resulted in two agonists, MSG010 MSG011, which did not display when screened against panel By radiolabel assay, MSG011 activated one order magnitude greater potency than pan MK-8722. A crystal structure complexed α2β1γ1 revealed similar binding mode SC4 potential importance interaction between 2-hydroxyl α2-Lys31 directing α2-selectivity. induced robust signalling mouse hepatocytes commonly used cell lines, most cases this occurred absence changes phosphorylation activation loop residue α-Thr172, classical marker AMP-induced activity. These findings will guide future design α2β2-selective hypothesise may avoid off-target complications associated indiscriminate throughout body.