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.