BAY-3827 and SBI-0206965: Potent AMPK Inhibitors That Paradoxically Increase Thr172 Phosphorylation
AMP-activated protein kinase (AMPK) is a vital element of a signalling path that senses energy stress and triggers a metabolic switch from anabolic processes and towards catabolic processes. There’s been an extended concentrate the pharmaceutical industry on the introduction of AMPK-activating drugs to treat metabolic disorders for example Diabetes type 2 and non-alcoholic fatty liver disease. However, recent findings claim that AMPK inhibitors may be effective for the treatment of certain cancers, especially lung adenocarcinomas, where the PRKAA1 gene (encoding the a1 catalytic subunit isoform of AMPK) is frequently amplified. Here, we study two potent AMPK inhibitors, BAY-3827 and SBI-0206965. Despite not carefully related structurally, treating cells with either drug suddenly caused increases in AMPK phosphorylation in the activating site, Thr172, although the phosphorylation of countless downstream targets in various subcellular compartments was completely inhibited. Surprisingly, the 2 inhibitors seem to promote Thr172 phosphorylation by different mechanisms: BAY-3827 mainly protects against Thr172 dephosphorylation, while SBI-0206965 also promotes phosphorylation by LKB1 at low concentrations, while growing cellular AMP:ATP ratios at greater concentrations. Because of its greater potency and less off-target effects, BAY-3827 has become the inhibitor preferred by cell studies, although its low bioavailability may limit its use within vivo.