Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

  • Science. 2017 Aug 4;357(6350):507-511. doi: 10.1126/science.aah5582.
Robert W Myers  1 ,  Hong-Ping Guan  2 ,  Juliann Ehrhart  3 ,  Aleksandr Petrov  2 ,  Srinivasa Prahalada  3 ,  Effie Tozzo  2 ,  Xiaodong Yang  2 ,  Marc M Kurtz  4 ,  Maria Trujillo  5 ,  Dinko Gonzalez Trotter  6 ,  Danqing Feng  7 ,  Shiyao Xu  8 ,  George Eiermann  5 ,  Marie A Holahan  6 ,  Daniel Rubins  6 ,  Stacey Conarello  5 ,  Xiaoda Niu  4 ,  Sandra C Souza  2 ,  Corin Miller  6 ,  Jinqi Liu  2 ,  Ku Lu  2 ,  Wen Feng  4 ,  Ying Li  2 ,  Ronald E Painter  4 ,  James A Milligan  4 ,  Huaibing He  8 ,  Franklin Liu  2 ,  Aimie Ogawa  4 ,  Douglas Wisniewski  4 ,  Rory J Rohm  2 ,  Liyang Wang  4 ,  Michelle Bunzel  6 ,  Ying Qian  2 ,  Wei Zhu  2 ,  Hongwu Wang  7 ,  Bindu Bennet  3 ,  Lisa LaFranco Scheuch  3 ,  Guillermo E Fernandez  3 ,  Cai Li  5 ,  Michael Klimas  6 ,  Gaochao Zhou  4 ,  Margaret van Heek  5 ,  Tesfaye Biftu  7 ,  Ann Weber  7 ,  David E Kelley  2 ,  Nancy Thornberry  2 ,  Mark D Erion  2 ,  Daniel M Kemp  2 ,  Iyassu K Sebhat  9
Affiliations
  • 1. In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA. [email protected] [email protected].
  • 2. Biology-Discovery, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  • 3. Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, PA 19486, USA.
  • 4. In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  • 5. In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  • 6. Translational Imaging and Biomarkers Departments, Merck Research Laboratories, West Point, PA 19486, USA.
  • 7. Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  • 8. PPDM Preclinical ADME Departments, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  • 9. Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA. [email protected] [email protected].
PMID: 28705990 DOI: 10.1126/science.aah5582
Abstract

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.

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