The structural requirements of 3,5-substituted oxindoles that determine selective AMPK or GSK3β inhibition

AMP-activated protein kinase (AMPK) acts as a central cellular sensor at the interface of metabolic and signaling networks, that supports cell survival in energetically unfavorable environments. Due to its role in the direct mediation of fatty acid oxidation <i>via</i> acetyl-CoA carboxylase 2 (ACC2), there has been intensive development of small molecule AMPK activators for the treatment of metabolic diseases, such as diabetes and non-alcoholic fatty liver disease. In cancer, AMPK inhibitors may be more effective in disrupting catabolic processes that support cancer cell survival and drug resistance. We have previously reported a structure-activity study of substituted oxindoles based on the multi-kinase inhibitor sunitinib to determine the structural requirements for AMPK inhibition and found that a 5-(2-cyanoethyl)-substituted oxindole displayed selectivity for AMPK over VEGFR-2. Interestingly, the GSK3β inhibitor AZD1080, a 5-cyano-oxindole, was also found to inhibit AMPK in a limited screen. Here, we report a further series of 3,5-substituted oxindoles that demonstrate that 5-cyano-oxindoles can inhibit both GSK3β and AMPK, but the 5-(2-cyanoethyl)-substitution and the orientation of the 3-substituent of the oxindole are critical determinants for AMPK inhibition and selectivity. These findings could have critical importance in evaluating metabolic targeting in cancer as GSK3β promotes anabolic pathways and suppresses AMPK activity.