The Centers for Disease Control and Prevention estimates more than 15% of adults in the United States, over 30 million Americans have chronic kidney disease (CKD). Podocytes are epithelial cells in the glomerulus whose major function is the maintenance of the kidney filtration barrier to prevent CKD. Furthermore, the prevalence of CKD in the Veteran population is a third higher than in the general population. Podocyte injury is implicated in diseases such as Focal Segmental Glomerular Sclerosis (FSGS). In these diseases, the podocyte loses characteristic morphologic features and the functional capacity to maintain the glomerular filtration barrier. In several recent studies, we reported the essential role of Krüppel-Like Factor 15 (KLF15), a kidney-enriched transcription factor, in maintaining podocyte actin cytoskeleton under cell stress. For instance, loss of function studies in preclinical proteinuric murine models demonstrated that KLF15 is required to prevent podocyte injury and the salutary benefits of glucocorticoids (GCs), the most common treatment for primary glomerulopathies, are mediated by KLF15. As well, the responsiveness to GCs in human primary glomerulopathies is associated with podocyte-specific expression of KLF15. Furthermore, induction of human KLF15 in podocytes attenuated kidney injury in proteinuric murine models, without the adverse sequelae of GCs. Collectively, these preclinical and clinical studies on the renoprotective effects of KLF15 induction motivated us to identify novel small molecule KLF15 agonists for kidney disease. We initially generated and conducted a cell-based high-throughput screening (HTS) to screen small molecules that induce KLF15 activity. Subsequent dose-escalating studies identified novel lead compounds with a half maximal effective concentration (EC50), in the optimal therapeutic window, required to induce KLF15 activity. Based on EC50 and druggability, we conducted Structure-Activity Relationship (SAR) on the lead compound K-7 and generated 16 lead analogues, of which BT501, BT502, BT503, BT514, and BT412 induced KLF15 promoter activity with or without cell stress. We also performed intial pharmacokinetic studies for K-7 in mice and also showed that human podocytes treated with K-7 and lead analogues attenuated podocyte injury in the setting of cell stress. Furthemore, RNA-seq of K-7 treated human podocytes shows inhibition of pathway IL-17RA-mediated actin cytoskeleton destabilization, thereby providing the rationale to utilize a mechanistic approach to optimize selectivity of KLF15 agonists. Finally, we observed that K-7 attenuated albuminuria and restored podocyte markers in a preclinical proteinuric murine model. Based on these compelling preliminary data and strong scientific rigor of prior research, we hypothesize that optimization of lead KLF15 agonists in preclinical studies will serve as a key therapeutic in proteinuric kidney diseases. We propose to test our hypothesis by (1) improving...