2 research outputs found
HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins
Small molecule-induced
protein degradation is an attractive strategy
for the development of chemical probes. One method for inducing targeted
protein degradation involves the use of PROTACs, heterobifunctional
molecules that can recruit specific E3 ligases to a desired protein
of interest. PROTACs have been successfully used to degrade numerous
proteins in cells, but the peptidic E3 ligase ligands used in previous
PROTACs have hindered their development into more mature chemical
probes or therapeutics. We report the design of a novel class of PROTACs
that incorporate small molecule VHL ligands to successfully degrade
HaloTag7 fusion proteins. These HaloPROTACs will inspire the development
of future PROTACs with more drug-like properties. Additionally, these
HaloPROTACs are useful chemical genetic tools, due to their ability
to chemically knock down widely used HaloTag7 fusion proteins in a
general fashion
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 <b>3i</b> is a potent hit (TBK1 DC<sub>50</sub> = 12 nM, <i>D</i><sub>max</sub> = 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