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更新于：2025-03-20

SGC-CAMKK2-1

更新于：2025-03-20

概要

概要

基本信息

药物类型

小分子化药

别名-

靶点

CAMKK2

作用方式

抑制剂

作用机制

CAMKK2 inhibitors(CAM kinase kinase inhibitor beta inhibitors)

治疗领域-

在研适应症-

非在研适应症-

原研机构

The University of North Carolina at Chapel Hill

在研机构

The University of North Carolina at Chapel Hill

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构/序列

分子式C26H23NO3

InChIKeyTXIYVFVMXNFNRX-UHFFFAOYSA-N

CAS号2561494-76-4

关联

100 项与 SGC-CAMKK2-1 相关的临床结果

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100 项与 SGC-CAMKK2-1 相关的转化医学

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100 项与 SGC-CAMKK2-1 相关的专利（医药）

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项与 SGC-CAMKK2-1 相关的文献（医药）

2023-09-01·Molecular metabolism

CaMKK2 is not involved in contraction-stimulated AMPK activation and glucose uptake in skeletal muscle.

Article

作者: Hellberg, Kristina ; Hafen, Paul S ; Agerholm, Marianne ; Hossain, Mohammad A ; Sakamoto, Kei ; Witczak, Carol A ; Sankar, Uma ; Ling, Naomi X Y ; Sermersheim, Tyler J ; Brault, Jeffrey J ; Oakhill, Jonathan S ; Ochala, Julien ; Addinsall, Alex B ; Bringas, Conchita Fraguas ; Negoita, Florentina ; Drewry, David H ; Larsen, Jeppe K ; Lewis, Christopher T A ; Deshmukh, Atul S ; Ahwazi, Danial ; Scott, John W

OBJECTIVEThe AMP-activated protein kinase (AMPK) gets activated in response to energetic stress such as contractions and plays a vital role in regulating various metabolic processes such as insulin-independent glucose uptake in skeletal muscle. The main upstream kinase that activates AMPK through phosphorylation of α-AMPK Thr172 in skeletal muscle is LKB1, however some studies have suggested that Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CaMKK2) acts as an alternative kinase to activate AMPK. We aimed to establish whether CaMKK2 is involved in activation of AMPK and promotion of glucose uptake following contractions in skeletal muscle.METHODSA recently developed CaMKK2 inhibitor (SGC-CAMKK2-1) alongside a structurally related but inactive compound (SGC-CAMKK2-1N), as well as CaMKK2 knock-out (KO) mice were used. In vitro kinase inhibition selectivity and efficacy assays, as well as cellular inhibition efficacy analyses of CaMKK inhibitors (STO-609 and SGC-CAMKK2-1) were performed. Phosphorylation and activity of AMPK following contractions (ex vivo) in mouse skeletal muscles treated with/without CaMKK inhibitors or isolated from wild-type (WT)/CaMKK2 KO mice were assessed. Camkk2 mRNA in mouse tissues was measured by qPCR. CaMKK2 protein expression was assessed by immunoblotting with or without prior enrichment of calmodulin-binding proteins from skeletal muscle extracts, as well as by mass spectrometry-based proteomics of mouse skeletal muscle and C2C12 myotubes.RESULTSSTO-609 and SGC-CAMKK2-1 were equally potent and effective in inhibiting CaMKK2 in cell-free and cell-based assays, but SGC-CAMKK2-1 was much more selective. Contraction-stimulated phosphorylation and activation of AMPK were not affected with CaMKK inhibitors or in CaMKK2 null muscles. Contraction-stimulated glucose uptake was comparable between WT and CaMKK2 KO muscle. Both CaMKK inhibitors (STO-609 and SGC-CAMKK2-1) and the inactive compound (SGC-CAMKK2-1N) significantly inhibited contraction-stimulated glucose uptake. SGC-CAMKK2-1 also inhibited glucose uptake induced by a pharmacological AMPK activator or insulin. Relatively low levels of Camkk2 mRNA were detected in mouse skeletal muscle, but neither CaMKK2 protein nor its derived peptides were detectable in mouse skeletal muscle tissue.CONCLUSIONSWe demonstrate that pharmacological inhibition or genetic loss of CaMKK2 does not affect contraction-stimulated AMPK phosphorylation and activation, as well as glucose uptake in skeletal muscle. Previously observed inhibitory effect of STO-609 on AMPK activity and glucose uptake is likely due to off-target effects. CaMKK2 protein is either absent from adult murine skeletal muscle or below the detection limit of currently available methods.

Cells

SGC-CAMKK2-1: A Chemical Probe for CAMKK2

Article

作者: Eduful, Benjamin ; Frigo, Daniel E. ; Couñago, Rafael M. ; Mukherjee, Debarati ; Lin, Chenchu ; Pulliam, Thomas L. ; Stork, Brittany ; Racioppi, Luigi ; Nay, Kevin ; Drewry, David H. ; Means, Anthony R. ; McDonnell, Donald P. ; York, Brian ; Scott, John W. ; Langendorf, Christopher G. ; O’Byrne, Sean ; Oakhill, Jonathan S. ; Gileadi, Carina ; Ramos, Priscila Zonzini ; Liang, Yi ; Hossain, Mohammad Anwar ; Awad, Dominik ; Gileadi, Opher ; Wells, Carrow ; Catta-Preta, Carolina Moura Costa

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

100 项与 SGC-CAMKK2-1 相关的药物交易

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