Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4

Kevin R W Ngoei; Christopher G Langendorf; Naomi X Y Ling; Ashfaqul Hoque; Swapna Varghese; Michelle A Camerino; Scott R Walker; Ylva E Bozikis; Toby A Dite; Ashley J Ovens; William J Smiles; Roxane Jacobs; He Huang; Michael W Parker; John W Scott; Mark H Rider; Richard C Foitzik; Bruce E Kemp; Jonathan B Baell; Jonathan S Oakhill

doi:10.1016/j.chembiol.2018.03.008

Structural Determinants for Small-Molecule Activation of Skeletal Muscle AMPK α2β2γ1 by the Glucose Importagog SC4

Cell Chem Biol. 2018 Jun 21;25(6):728-737.e9. doi: 10.1016/j.chembiol.2018.03.008. Epub 2018 Apr 12.

Authors

Kevin R W Ngoei¹, Christopher G Langendorf², Naomi X Y Ling³, Ashfaqul Hoque³, Swapna Varghese⁴, Michelle A Camerino⁵, Scott R Walker⁵, Ylva E Bozikis⁵, Toby A Dite³, Ashley J Ovens⁶, William J Smiles³, Roxane Jacobs⁷, He Huang⁸, Michael W Parker⁹, John W Scott¹⁰, Mark H Rider⁷, Richard C Foitzik¹¹, Bruce E Kemp¹⁰, Jonathan B Baell¹², Jonathan S Oakhill¹³

Affiliations

¹ Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia.
² Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia. Electronic address: clangendorf@svi.edu.au.
³ Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia.
⁴ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Cancer Therapeutics CRC (CTx) Pty Ltd, Level 3, 343 Royal Parade, Parkville, VIC 3052, Australia.
⁶ Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000, Australia.
⁷ Université catholique de Louvain (UCL), de Duve Institute, Avenue Hippocrate 75 bte 74.02, 1200 Brussels, Belgium.
⁸ Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
⁹ ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3052, Australia.
¹⁰ Protein Chemistry & Metabolism, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000, Australia.
¹¹ Cancer Therapeutics CRC (CTx) Pty Ltd, Level 3, 343 Royal Parade, Parkville, VIC 3052, Australia; MecRX Pty Ltd, Level 9, 31 Queen Street, Melbourne, VIC 3000, Australia.
¹² Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
¹³ Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, VIC 3065, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC 3000, Australia. Electronic address: joakhill@svi.edu.au.

PMID: 29657085
DOI: 10.1016/j.chembiol.2018.03.008

Abstract

The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose "importagog" to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated α2β2γ1 and α2β1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and β2-Asp111, which provide a design paradigm for β2-AMPK therapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2-AMPK therapeutics.

Keywords: AMP-activated protein kinase; X-ray crystallography; diabetes; drug development; glucose disposal; importagog; metabolism; secretagog.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Animals
Benzoates / chemical synthesis
Benzoates / chemistry
Benzoates / pharmacology*
COS Cells
Cell Line
Chlorocebus aethiops
Crystallography, X-Ray
Enzyme Activation
Glucose / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Molecular
Molecular Structure
Muscle, Skeletal / drug effects*
Muscle, Skeletal / metabolism
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Rats
Rats, Wistar
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*

Substances

Benzoates
Pyridines
Small Molecule Libraries
AMP-Activated Protein Kinases
Glucose