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

J Med Chem. 2018 Jan 25;61(2):583-598. doi: 10.1021/acs.jmedchem.7b00635. Epub 2017 Jul 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Fluorescence Polarization
  • Genes, ras
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Molecular Structure
  • Mutation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteolysis / drug effects*
  • RNA Interference
  • Structure-Activity Relationship
  • Von Hippel-Lindau Tumor Suppressor Protein / chemistry
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*


  • Von Hippel-Lindau Tumor Suppressor Protein
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • IKBKE protein, human
  • VHL protein, human