Despite advances in the treatment of acute myeloid leukemia (AML), <30% of patients achieve long-term disease-free survival (DFS) and durable treatment options are needed. Our studies and those of others, have shown that AML cells have a dynamic metabolism mediated by AMPK activity that supports cancer survival and drug resistance. Interestingly, AMPK activity has been implicated in the clinical resistance of the Bcl-2 inhibitor venetoclax that has been FDA-approved for the treatment of a range of blood cancers, including AML. Therefore, AMPK inhibition may compromise AML cell viability and sensitize them to venetoclax. We have examined the effect of commercially available AMPK inhibitors, including the dual AMPK/RSK inhibitor BAY3827, on the viability of MOLM-13 and MOLM-14 AML cell lines as single agents and in combination with venetoclax. Our initial structure-activity studies using the oxindole heterocycle as a core to develop novel AMPK inhibitors demonstrated that improved AMPK selectivity and potency was possible. Here, we present a refined series of oxindoles designed to interact with the DFG motif within the ATP-binding site of the catalytic α-subunit to improve inhibitory potency and also limit binding to RSK. Our studies provide important structural information for the further AMPK inhibitor development and potential insights into structural modifications that may limit metabolism and allow cancer-selective AMPK targeting. Further studies are required to determine the impact of AMPK inhibition in AML as specific populations, such as leukemic stem cells (LSCs), may be more sensitive to metabolic targeting and this may be important for staging therapy.