Novel Activators of AMP-activated Protein Kinase

University of Pittsburgh researchers have identified a library of small molecules found to promote activity of AMP-activated Protein Kinase (AMPK), a key regulator of several metabolic pathways.

Description

AMPK regulates many processes in the body including glucose uptake, mitochondrial biogenesis, and protein synthesis. AMPK is involved in disorders including cancer, and metabolic and inflammatory diseases. Previous work by the inventors has identified a novel target to inhibit the degradation of AMPK, the Fbxo48 cavity on the Skp-Cullin-F box (SCF) complex of ubiquitin E3 Ligases. Initial in silico analysis and structure-activity relationship (SAR) studies led to the synthesis of compounds that increased cellular levels of activated AMPK. Further work has developed more compounds, many requiring <1 µM dosages to increase AMPK activation, suggesting these are highly efficient AMPK activators with reduced risk of side effects.

Applications

1. Metabolic diseases
2. Inflammatory conditions
3. Cancer

Advantages

Interaction with ubiquitin degrades activated AMPK. These novel compounds block ubiquitination, a new mechanism for promoting AMPK activity through protection against degradation. They are active at nanomolar concentrations, reducing the risk of side effects and potentially increasing efficacy compared to existing treatments.

Invention Readiness

Previous work identified Fbxo48 as a key target to inhibit the degradation of activated AMPK. Initial in silico and SAR studies identified organic compounds to enhance cellular levels of AMPK. Additional work has identified a further 49 novel compounds and one previously known compound that can increase cellular levels of activated AMPK by at least 30%. Seven of these compounds were effective at <1 µM, suggesting an effective treatment with a lower risk of adverse effects.

IP Status

https://patents.google.com/patent/US20220340533A1