Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1
Craig M. Crews, Brian D. Hamman, Taavi K. Neklesa, Alicia Morgan, Jing Wang, Dominico Vigil, Andrew P. Crew, Kam Siu, Kanak Raina, Caterina Ferraro, Yevgeniy V. Serebrenik, Kevin G. Coleman, Yimin Qian, James D. Winkler, Hanqing Dong
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00635

DOI: 10.1021/acs.jmedchem.7b00635

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