Small-molecule inhibitors of SGK1: Structural basis, structure-activity relationships, and therapeutic perspectives

SGK1 (serum/glucocorticoid-regulated kinase 1) is an AGC family serine/threonine kinase with a pronounced inducible activation profile; its expression and activation are governed by hormonal stimuli and cellular stress. When PI3K-AKT signaling is constrained, SGK1 can function as an alternative node that sustains cell survival and stress adaptation. Its dysregulation has been linked to tumor drug resistance, salt-sensitive hypertension, cardiovascular disease, fibrosis, and neurodegenerative disorders, supporting its potential as a therapeutic target. As understanding of SGK1 biology and structure has deepened, medicinal chemistry efforts have accelerated. The entry of Thryv Therapeutics' LQT-1213 and THRV-1268 into clinical trials, together with advances in screening and methodological strategies, has moved selective SGK1 inhibitor development into a phase of rapid progress. This review summarizes the structural features and activation mechanism of SGK1, surveys its signaling and disease associations, and analyzes the chemical scaffolds, structure-activity relationships, and activity profiles of representative inhibitors. On this basis, it discusses recurring bottlenecks in current development and alternative strategies for improving selectivity and translational potential, highlighting future directions for SGK1-targeted inhibitors with improved selectivity and clinical translatability.