Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive cyst formation and renal failure. Tank-binding kinase 1 (TBK1), a key regulator of inflammation, represents a promising target for ADPKD treatment. In this study, we designed and synthesized a series of TBK1 degraders, including both PROTACs and molecular glues. Among the compounds evaluated, degrader 30 demonstrated superior efficacy, inducing TBK1 degradation in a dose- and time-dependent manner. Mechanistic studies revealed that 30 mediates TBK1 degradation through the ubiquitin–proteasome system via E3 ligase RNF126. Compound 30 effectively inhibited cyst growth and alleviated inflammation in MDCK cysts and in a kidney-specific Pkd1 knockout mouse model. Treatment with 30 reduced the levels of key inflammatory markers, such as Ccl2, IFNβ, and IL-6, which are implicated in ADPKD pathogenesis. These findings highlight the therapeutic potential of TBK1 degradation as a novel strategy for treating ADPKD by simultaneously targeting cyst formation and inflammation.