Brain Permeable SGK1 Inhibitors: A Promising Therapeutic Strategy for Neurodegenerative Diseases
Enrique Madruga, Alfonso Garcia-Rubia, Carlos Sanchez-Nuñez, Loreto Martinez-Gonzalez, Ana María Fernandez-Escamilla, Isabel Lastres-Becker, Carmen Gil, Ana Martinez
TL;DR
Researchers developed brain-penetrant inhibitors for SGK1, a promising target for treating neurodegenerative diseases like Alzheimer's.
Contribution
A new family of brain-permeable SGK1 inhibitors was developed for potential use in neurological disorders.
Findings
A medicinal chemistry program produced brain-penetrant SGK1 inhibitors.
These inhibitors serve as chemical probes to study SGK1's role in neurodegeneration.
SGK1 is highlighted as a potential therapeutic target for Alzheimer's disease.
Abstract
A major challenge in modern medicine is developing new therapies for aging-related diseases such as neurodegenerative disorders, whose prevalence increases with longer life expectancy. Although kinase inhibitors have achieved clinical success, their development for central nervous system (CNS) disorders remains limited due to the complexity of kinase networks and poor blood–brain barrier (BBB) permeability. Serum/glucocorticoid-regulated kinase 1 (SGK1) participates in multiple signaling pathways but remains an underexplored target in neurodegeneration. Following a mixed ligand- and structure-based virtual screening, we have previously identified a brain-penetrant SGK1 inhibitor. A medicinal chemistry program based on hit expansion and optimization for BBB permeability reported here has generated a new family of SGK1 inhibitors as chemical probes that enable the investigation of SGK1’s…
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Taxonomy
TopicsIon Transport and Channel Regulation · Neuroscience and Neuropharmacology Research · Receptor Mechanisms and Signaling