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

Abstract

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.

Keywords:

• Protein kinase inhibitors
• SGK1
• virtual screening
• mitophagy
• neurodegeneration

Acknowledgements

The authors thank Dr. Anne Simonsen for kindly provide the U2O2 cell lines and Ian Ganley for providing the SH-SY5Y MitoQC cells.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported by the European Comission H2020-MSCA-ITN-2017 program (grant no. 765912, DRIVE Project), Ministerio de Ciencia e Investigación (grant PID2019-105600RB-I00), ISCiii (grant CB18/05/00040, CIBERNED) and CSIC Interdisciplinary Thematic Platform (PTI+) NEURO-AGINGl+ (PTI-NEURO-AGING+), Fondos recuperación PT + Neuroaging.