Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD

  • Sci Rep. 2017 Sep 18;7(1):11793. doi: 10.1038/s41598-017-12139-3.
Brian York  1  2 ,  Feng Li  3  4 ,  Fumin Lin  3 ,  Kathrina L Marcelo  3 ,  Jianqiang Mao  3 ,  Adam Dean  3 ,  Naomi Gonzales  3  5 ,  David Gooden  6 ,  Suman Maity  3  7 ,  Cristian Coarfa  3  7 ,  Nagireddy Putluri  3 ,  Anthony R Means  3  5  7
Affiliations
  • 1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 2. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 4. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA.
  • 5. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
  • 6. Department of Chemistry, Duke University, Durham, NC, USA.
  • 7. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
PMID: 28924233 DOI: 10.1038/s41598-017-12139-3
Abstract

Binding of calcium to its intracellular receptor Calmodulin (CaM) activates a family of CA2+/CaM-dependent protein kinases. CaMKK2 (CA2+/CaM-dependent protein kinase kinase 2) is a central member of this kinase family as it controls the actions of a CaMK cascade involving CaMKI, CaMKIV or AMPK. CaMKK2 controls Insulin signaling, metabolic homeostasis, inflammation and Cancer cell growth highlighting its potential as a therapeutic target for a variety of diseases. STO-609 is a selective, small molecule inhibitor of CaMKK2. Although STO-609 has been used extensively in vitro and in cells to characterize and define new mechanistic functions of CaMKK2, only a few studies have reported the in vivo use of STO-609. We synthesized functional STO-609 and assessed its pharmacological properties through in vitro (kinase assay), ex vivo (human liver microsomes) and in vivo (mouse) model systems. We describe the metabolic processing of STO-609, its toxicity, pharmacokinetics and bioavailability in a variety of mouse tissues. Utilizing these data, we show STO-609 treatment to inhibit CaMKK2 function confers protection against non-alcoholic fatty liver disease. These data provide a valuable resource by establishing criteria for use of STO-609 to inhibit the in vivo functions of CaMKK2 and demonstrate its utility for treating metabolically-related hepatic disease.