WCN26-7552 Development of Potent and Selective NUAK1 Inhibitors that Attenuate TGF-β–Induced and UUO-Driven Renal Fibrosis via YAP Pathway Modulation

Kidney fibrosis represents a self-perpetuating injury pathway that is activated in nearly all forms of chronic kidney disease (CKD) leading to end-stage renal disease (ESRD), yet no renal antifibrotic therapy has been developed to date. NUAK1, a member of the AMP-related kinase family, is upregulated in fibrotic tissues and correlated with progressive dysfunction in human transplant kidneys. Mechanistically, NUAK1 activates YAP/TAZ transcriptional activity by destabilizing a Hippo pathway kinase LATS1.