A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α‐mediated aerobic glycolysis

Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion, and high metastasis. Currently available US Food and Drug Administration (FDA)‐approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT‐1015, that allosterically activated adenosine monophosphate‐activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT‐1015 was shown to bind the AMPK α and β‐subunit interface, thereby exposing the kinase α domain to the upstream kinases, resulting in the increased AMPK activity. SCT‐1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo. We further found that AMPK formed protein complexes with hypoxia‐inducible factor 1‐alpha (HIF1α) and that SCT‐1015‐activated AMPK promoted hydroxylation of HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin‐proteasome system. With declined HIF1α abundance, many glycolysis‐related enzymes were downregulated, suppressing aerobic glycolysis, and promoting oxidative phosphorylation. These results indicated that SCT‐1015 channeled HCC cells into an unfavorable metabolic status. Overall, we reported SCT‐1015 as a direct activator of AMPK signaling that held therapeutic potential in HCC. In HCC, the transcription factor HIF1α regulates the expression of HK and PDK, leading to the Warburg phenotype, which promotes HCC progression. Under treatment with SCT‐1015, a novel AMPK activator, the HIF1α protein abundance was reduced through the increased HIF1α protein degradation (ERK/PHD‐dependent HIF1α hydroxylation) and the decline of the HIF1α protein synthesis (mTORC1 signaling), eliciting an anti‐Warburg effect and an anti‐HCC effect.