Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1

Proteolysis
targeting chimeras (PROTACs) are bifunctional molecules
that recruit an E3 ligase to a target protein to facilitate ubiquitination
and subsequent degradation of that protein. While the field of targeted
degraders is still relatively young, the potential for this modality
to become a differentiated and therapeutic reality is strong, such
that both academic and pharmaceutical institutions are now entering
this interesting area of research. In this article, we describe a
broadly applicable process for identifying degrader hits based on
the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have
generalized the key structural elements associated with degradation
activities. Compound 3i is a potent hit (TBK1 DC50 = 12 nM, Dmax = 96%) with excellent
selectivity against a related kinase IKKε, which was further
used as a chemical tool to assess TBK1 as a target in mutant K-Ras
cancer cells.