Pharmacological Inhibition of CaMKK2 with the Selective Antagonist STO-609 Regresses NAFLD

Overview

Journal Sci Rep

Specialty Science

Date 2017 Sep 20

PMID 28924233

Citations 28

Authors

Brian York

Feng Li

Fumin Lin

Kathrina L Marcelo

Jianqiang Mao

Adam Dean

Naomi Gonzales

David Gooden

Suman Maity

Cristian Coarfa

Nagireddy Putluri

Anthony R Means

Affiliations

Soon will be listed here.

Abstract

Binding of calcium to its intracellular receptor calmodulin (CaM) activates a family of Ca/CaM-dependent protein kinases. CaMKK2 (Ca/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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References

Kukimoto-Niino M, Yoshikawa S, Takagi T, Ohsawa N, Tomabechi Y, Terada T . Crystal structure of the Ca²⁺/calmodulin-dependent protein kinase kinase in complex with the inhibitor STO-609. J Biol Chem. 2011; 286(25):22570-9. PMC: 3121401. DOI: 10.1074/jbc.M111.251710. View

Carpenter T, Kirshner D, Lau E, Wong S, Nilmeier J, Lightstone F . A method to predict blood-brain barrier permeability of drug-like compounds using molecular dynamics simulations. Biophys J. 2014; 107(3):630-641. PMC: 4129472. DOI: 10.1016/j.bpj.2014.06.024. View

von Rundstedt F, Rajapakshe K, Ma J, Arnold J, Gohlke J, Putluri V . Integrative Pathway Analysis of Metabolic Signature in Bladder Cancer: A Linkage to The Cancer Genome Atlas Project and Prediction of Survival. J Urol. 2016; 195(6):1911-9. PMC: 4861129. DOI: 10.1016/j.juro.2016.01.039. View

Yoon W, Sandoval H, Nagarkar-Jaiswal S, Jaiswal M, Yamamoto S, Haelterman N . Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration. Neuron. 2016; 93(1):115-131. PMC: 5242142. DOI: 10.1016/j.neuron.2016.11.038. View

Keltner N, Opara I . Psychotropic drug interactions with grapefruit juice. Perspect Psychiatr Care. 2002; 38(1):31-3. View

Cho U, Park E, Dong M, Park B, Kim K, Kim K . Tight-binding inhibition by alpha-naphthoflavone of human cytochrome P450 1A2. Biochim Biophys Acta. 2003; 1648(1-2):195-202. DOI: 10.1016/s1570-9639(03)00148-1. View

Jamieson Jr G, Vanaman T . Calcium-dependent affinity chromatography of calmodulin on an immobilized phenothiazine. Biochem Biophys Res Commun. 1979; 90(3):1048-56. DOI: 10.1016/0006-291x(79)91932-6. View

Aramburu J, Rao A, Klee C . Calcineurin: from structure to function. Curr Top Cell Regul. 2000; 36:237-95. DOI: 10.1016/s0070-2137(01)80011-x. View

Wishart D, Tzur D, Knox C, Eisner R, Guo A, Young N . HMDB: the Human Metabolome Database. Nucleic Acids Res. 2007; 35(Database issue):D521-6. PMC: 1899095. DOI: 10.1093/nar/gkl923. View

10.

Marcelo K, Means A, York B . The Ca(2+)/Calmodulin/CaMKK2 Axis: Nature's Metabolic CaMshaft. Trends Endocrinol Metab. 2016; 27(10):706-718. PMC: 5035586. DOI: 10.1016/j.tem.2016.06.001. View

11.

Massie C, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L . The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 2011; 30(13):2719-33. PMC: 3155295. DOI: 10.1038/emboj.2011.158. View

12.

Marcelo K, Ribar T, Means C, Tsimelzon A, Stevens R, Ilkayeva O . Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism. Mol Endocrinol. 2016; 30(5):557-72. PMC: 4853564. DOI: 10.1210/me.2016-1021. View

13.

Kettner N, Voicu H, Finegold M, Coarfa C, Sreekumar A, Putluri N . Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis. Cancer Cell. 2016; 30(6):909-924. PMC: 5695235. DOI: 10.1016/j.ccell.2016.10.007. View

14.

Bhowmik S, Ramirez-Pena E, Arnold J, Putluri V, Sphyris N, Michailidis G . EMT-induced metabolite signature identifies poor clinical outcome. Oncotarget. 2015; 6(40):42651-60. PMC: 4767460. DOI: 10.18632/oncotarget.4765. View

15.

Kang Y, Putluri N, Maity S, Tsimelzon A, Ilkayeva O, Mo Q . CAPER is vital for energy and redox homeostasis by integrating glucose-induced mitochondrial functions via ERR-α-Gabpa and stress-induced adaptive responses via NF-κB-cMYC. PLoS Genet. 2015; 11(4):e1005116. PMC: 4382186. DOI: 10.1371/journal.pgen.1005116. View

16.

Park J, Vithayathil S, Kumar S, Sung P, Dobrolecki L, Putluri V . Fatty Acid Oxidation-Driven Src Links Mitochondrial Energy Reprogramming and Oncogenic Properties in Triple-Negative Breast Cancer. Cell Rep. 2016; 14(9):2154-2165. PMC: 4809061. DOI: 10.1016/j.celrep.2016.02.004. View

17.

Putluri N, Shojaie A, Vasu V, Nalluri S, Vareed S, Putluri V . Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells. PLoS One. 2011; 6(7):e21417. PMC: 3138744. DOI: 10.1371/journal.pone.0021417. View

18.

Woods A, Dickerson K, Heath R, Hong S, Momcilovic M, Johnstone S . Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005; 2(1):21-33. DOI: 10.1016/j.cmet.2005.06.005. View

19.

Terunuma A, Putluri N, Mishra P, Mathe E, Dorsey T, Yi M . MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2013; 124(1):398-412. PMC: 3871244. DOI: 10.1172/JCI71180. View

20.

Kunze K, TRAGER W . Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline. Chem Res Toxicol. 1993; 6(5):649-56. DOI: 10.1021/tx00035a009. View