Serum- and glucocorticoid-induced kinase 1, a new therapeutic target for autophagy modulation in chronic diseases

ABSTRACT

Introduction: Autophagy, a basic cellular degradation pathway essential for survival, is altered both in aging and in many chronic human diseases, including infections, cancer, heart disease, and neurodegeneration. Identifying new therapeutic targets for the control and modulation of autophagy events is therefore of utmost importance in drug discovery. Serum and glucocorticoid activated kinase 1 (SGK1), known for decades for its role in ion channel modulation, is now known to act as a switch for autophagy homeostasis, and has emerged as a novel and important therapeutic target likely to attract considerable research attention in the coming years.

Areas covered: In this general review of SGK1 we describe the kinase’s structure and its roles in physiological and pathological contexts. We also discuss small-molecule modulators of SGK1 activity. These modulators are of particular interest to medicinal chemists and pharmacists seeking to develop more potent and selective drug candidates for SGK1, which, despite its key role in autophagy, remains relatively understudied.

Expert opinion: The main future challenges in this area are (i) deciphering the role of SGK1 in selective autophagy processes (e.g. mitophagy, lipophagy, and aggrephagy); (ii) identifying selective allosteric modulators of SGK1 with specific biological functions; and (iii) conducting first-in-man clinical studies.

KEYWORDS:

• SGK1
• autophagy
• kinase inhibitors
• therapeutic target
• neurodegenerative diseases

Article Highlights

• SGK1 acts as a switch for autophagy modulation.

• SGK1 is a potential therapeutic target for increasing autophagy in conditions in which this process is deficient.

• The lack of severe side effects in SGK1 knock-out mice suggests a favorable therapeutic window for SGK1 inhibitors.

• Currently available SGK1 inhibitors are useful research tools and serve as starting points for drug candidate optimization.

• Development of allosteric modulators of SGK1 with enhanced kinase specificity would constitute an important advance in the field.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Funding support was provided by European Union (EU) (H2020-MSCA-ITN-2017 (grant no. 765912, DRIVE Driving next generation autophagy researchers towards translation); the Autonomous Community of Madrid (CM) (grant no. BMD-3813 ELA_Madrid); and Spanish Ministry of Research and Science (MCIU) and State Research Agency (AEI) (grant numbers PGC2018-098557-B-I00 to P.B. and SAF2016-76693-R to A.M)).