Serum- and glucocorticoid-regulated kinases (SGKs) play important roles in the regulation of cellular signaling pathways, which have been reported to play crucial roles in cancer progression. To discover new scaffolds of SGK inhibitors, an in-house kinase-focused library was screened against SGK1 and numerous hit compounds were identified. Among the active hits, 12 compounds were found to be various substituted thiazolidine-2,4-dione (TZD) derivatives. Structure-activity relationship (SAR) and structure-based modeling studies revealed that some structural features such as TZD, the hydroxyl group, and the amino group were important for binding to SGK1.