Pharmacological AMPK inhibitor: the hidden side of Compound C

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Compound C is a cell-permeable pyrrazolopyrimidine compound that can act as a reversible and ATP-competitive inhibitor of AMPK (Zhou et al., 2001). This compound is being used increasingly to inhibit AMPK in cell-based assays. However, several studies have reported inhibition of various biological events by Compound C independently of AMPK inhibition such as inhibition of the hypoxic activation of HIF-1 by suppressing mitochondrial generated reactive oxygen species (ROS) (Emerling et al., 2007) and proliferation of preadipocytes by increasing p21 levels (Nam et al., 2008). Furthermore, Compound C does not inhibit AMPK activation in response to all stimuli. Thus, this pharmacological inhibitor blunted the AICAR-induced but not the dinitrophenol-induced (Fryer et al., 2002) or the LPS-induced (Labuzek et al., 2010) activation of AMPK. Further investigation showed that Compound C inhibits the adenosine transporter (Fryer et al., 2002), the primary transporter for the uptake of AICAR into cells, suggesting that this pharmacological inhibitor should not be used to demonstrate AMPK-dependent effects of AICAR. Lastly, Compound C appears to inhibit a number of other protein kinases with lower IC₅₀ values than AMPK indicating that this compound could certainly have ‘off-target’ effects (Bain et al., 2007). However, despite the uncertain specificity of this pharmacological inhibitor, various reports suggest that in specific circumstances Compound C inhibits AMPK with expected results. For example, the genetic approach combined with the pharmacological approach further confirmed the AMPK-specific action of Compound C during stroke as the effect of this pharmacological inhibitor was lost in AMPKa2 knockout mice (Li et al., 2007).