Identification of a new structural family of SGK1 inhibitors as potential neuroprotective agents

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 38; no. 1; p. 2153841
• Main Authors: Maestro, Ines, Madruga, Enrique, Boya, Patricia, Martínez, Ana
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.12.2023; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Apoptosis; Autophagy; Blood-brain barrier; Brain research; Glucose; Hydrogen bonds; Inflammation; Kinases; Ligands; Medical research; Mitophagy; Neurodegeneration; Neuroprotection; Neuroprotective agents; Neuroprotective Agents - pharmacology; Protein kinase inhibitors; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein-serine/threonine kinase; Proteins; Research Paper; SGK1; virtual screening; neurodegeneration; mitophagy; virtual screening; Protein kinase inhibitors; SGK1
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2022.2153841

SGK1 is a serine/threonine kinase involved in several neurodegenerative-related pathways such as apoptosis, neuroinflammation, ionic channel regulation, and autophagy, among others. Despite its potential role as a pharmacological target against this kind of diseases, there are no reported inhibitors able to cross the BBB so far, being a field yet to be explored. In this context, a structure-based virtual screening against this kinase was performed, pointing out the deazapurine moiety as an interesting and easy-to-derivatize scaffold. Moreover, these inhibitors are able to i) exert neuroprotection in an in vitro model of AD and ii) block mitophagy in a PRKN-independent manner, reinforcing the hypothesis of SGK1 inhibitors as neuroprotective chemical tools.