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.