2. Academic Validation
  3. Brain Permeable SGK1 Inhibitors: A Promising Therapeutic Strategy for Neurodegenerative Diseases

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

  • J Med Chem. 2026 Mar 26;69(6):6790-6815. doi: 10.1021/acs.jmedchem.5c03050.
Enrique Madruga 1 2,  Alfonso Garcia-Rubia 1,  Carlos Sanchez-Nuñez 1,  Loreto Martinez-Gonzalez 1 2,  Ana María Fernandez-Escamilla 3,  Isabel Lastres-Becker 2 4 5,  Carmen Gil 1 2,  Ana Martinez 1 2
Affiliations

Affiliations

  • 1 Centro de Investigaciones Biológicas "Margarita Salas"─CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
  • 2 Centro de Investigación Biomédica en Red en Enfermedades Neurodegeneartivas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain.
  • 3 Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, 03202 Elche, Alicante, Spain.
  • 4 Instituto de Investigaciones Biomédica "Sols-Morreale"─CSIC/UAM, Arturo Duperier 4, 28039 Madrid, Spain.
  • 5 Instituto de Investigación Sanitaria La Paz (IdiPaz), Paseo de la Castellana, 261, 28046 Madrid, Spain.
PMID: 41837733 DOI: 10.1021/acs.jmedchem.5c03050
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 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.

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