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

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• Aging-related diseases, including neurodegenerative disorders, pose a significant challenge in modern medicine.
• Kinase inhibitors are successful therapies, but their application in central nervous system (CNS) disorders is limited by complex signaling networks and poor blood-brain barrier (BBB) penetration.
• Serum/glucocorticoid-regulated kinase 1 (SGK1) is an underexplored target in neurodegeneration, despite its role in various signaling pathways.

Purpose of the Study:

• To identify and optimize brain-penetrant inhibitors of SGK1 for potential therapeutic use in neurological disorders.
• To develop chemical probes for investigating the role of SGK1 in neurodegeneration.
• To establish SGK1 as a viable therapeutic target for neurodegenerative diseases like Alzheimer's disease.

Main Methods:

• Utilized a combination of ligand- and structure-based virtual screening to identify an initial SGK1 inhibitor.
• Conducted a medicinal chemistry program focused on hit expansion and optimization for enhanced BBB permeability.
• Generated a novel family of SGK1 inhibitors.

Main Results:

• Identified a brain-penetrant SGK1 inhibitor through virtual screening.
• Optimized the initial hit to create a new family of SGK1 inhibitors with improved properties.
• Developed chemical probes that facilitate the study of SGK1 in neurological contexts.
• Demonstrated the potential of these inhibitors as starting points for drug development.

Conclusions:

• SGK1 is a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.
• The newly developed SGK1 inhibitors serve as valuable tools for research and potential drug leads.
• Medicinal chemistry optimization can overcome BBB permeability challenges for CNS drug development.