University of Pittsburgh researchers have identified new small molecules to promote AMP-activated Protein Kinase (AMPK) activity, a key regulator of several metabolic pathways. By discovering a key active site on AMPK, and subsequent computational screening of millions of compounds, a series of small molecules have been identified.
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, with AMPK activation successfully used to manage type 2 diabetes. Through identification and analysis of active sites on AMPK, a novel mechanism of AMPK activation has been discovered, potentially allowing for new treatment approaches to many of the medical conditions linked with AMPK.
Applications
1. Metabolic diseases
2. Sepsis
3. Cancer
Advantages
While metformin (no capital letter for generic names) and phenformin have been used to activate AMPK successfully, the mechanism of action remains unknown; other AMPK activators are known to interact with a binding cavity in one of the three subunits of AMPK. All require millimolar concentrations of the active substance and can have considerable side effects in some circumstances.
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 with existing treatments.
Invention Readiness
In vivo studies show these First-in-Class F-box inhibitors increase AMPK activity at nanomolar concentrations. Further work is required to optimize the chemical structure and assess efficacy in humans.
IP Status
https://patents.google.com/patent/US11673853B2
