Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD.
Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD.
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DOI：
10.1038/s41598-017-12139-3
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发表时间：
2017-09-18
影响因子：
4.6
通讯作者：
Means AR
中科院分区：
文献类型：
--
作者：
York B;Li F;Lin F;Marcelo KL;Mao J;Dean A;Gonzales N;Gooden D;Maity S;Coarfa C;Putluri N;Means AR
钙离子与其细胞内受体钙调素（CaM）的结合激活了一个Ca 2 +/CaM依赖性蛋白激酶家族。CaMKK 2（Ca 2 +/CaM依赖性蛋白激酶激酶2）是该激酶家族的核心成员，因为它控制涉及CaMKI、CaMKIV或AMPK的CaMK级联的作用。CaMKK 2控制胰岛素信号传导、代谢稳态、炎症和癌细胞生长，突出了其作为多种疾病的治疗靶点的潜力。STO-609是CaMKK 2的选择性小分子抑制剂。尽管STO-609已在体外和细胞中广泛用于表征和定义CaMKK 2的新机制功能，但只有少数研究报道了STO-609的体内使用。我们合成了功能性STO-609，并通过体外（激酶测定）、离体（人肝微粒体）和体内（小鼠）模型系统评估其药理学特性。我们描述了STO-609的代谢过程，其毒性，药代动力学和生物利用度在各种小鼠组织。利用这些数据，我们表明STO-609治疗抑制CaMKK 2功能可保护非酒精性脂肪肝。这些数据通过建立使用STO-609抑制CaMKK 2的体内功能的标准提供了有价值的资源，并证明了其用于治疗代谢相关肝病的效用。
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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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
4.1
作者：
KUNZE, KL;TRAGER, WF
通讯作者：
TRAGER, WF
影响因子：
--
作者：
Marcelo, Kathrina L.;Ribar, Thomas;York, Brian
通讯作者：
York, Brian
影响因子：
16.6
作者：
Kaushik AK;Shojaie A;Panzitt K;Sonavane R;Venghatakrishnan H;Manikkam M;Zaslavsky A;Putluri V;Vasu VT;Zhang Y;Khan AS;Lloyd S;Szafran AT;Dasgupta S;Bader DA;Stossi F;Li H;Samanta S;Cao X;Tsouko E;Huang S;Frigo DE;Chan L;Edwards DP;Kaipparettu BA;Mitsiades N;Weigel NL;Mancini M;McGuire SE;Mehra R;Ittmann MM;Chinnaiyan AM;Putluri N;Palapattu GS;Michailidis G;Sreekumar A
通讯作者：
Sreekumar A
影响因子：
50.3
作者：
Kettner NM;Voicu H;Finegold MJ;Coarfa C;Sreekumar A;Putluri N;Katchy CA;Lee C;Moore DD;Fu L
通讯作者：
Fu L