Lifestyles that emphasize exercise and caloric restriction effect an increase in the activity of 5'-adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolic and energy homeostasis. This favorable enhancement curtails risks in developing chronic metabolic diseases like type-2 diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatoheptatitis (NASH), and cancers, even decelerating the aging process. As such, targeting AMPK is emerging as a promising avenue for therapeutic intervention -the aim being to emulate the low energy state that is conducive to combating diseases arising from the destabilizing imbalance between nutrient intake (i.e., high-calorie diets) and energy expenditure (i.e., increasingly sedentary routines). Nearly all research efforts have focused on developing activators of AMPK, while their corresponding inhibitors remain underexplored. In fact, there are instances where AMPK promotes tumor cell survival and that its deficiency represses tumor growth. Therefore, the ability to regulate AMPK levels, including its inhibition, can have important implications for advancing cancer treatments. Controlling AMPK can also be developed into a strategy for modulating autophagy, a metabolic process that degrades damaged organelles and is associated with a wide variety of diseases. 4 In contrast to the relatively abundant number of synthetic molecules and natural products that act as AMPK activators, there are only three compounds known to inhibit AMPK, 3b all of which are multikinase inhibitors (Figure 1a).