2. Academic Validation
  3. Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD

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

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.

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