Brain Permeable SGK1 Inhibitors: A Promising Therapeutic Strategy for Neurodegenerative Diseases

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
role in neurological disorders and serve as promising starting points
for drug development. These findings highlight SGK1 as a potential
therapeutic target for neurodegenerative diseases, such as Alzheimer’s
disease.