Abstract

Targeted protein degradation
with monofunctional molecules or bifunctional ones such as PROteolysis-TArgeting Chimeras (PROTACs) has evolved as an exciting and
promising approach to modulate and inhibit disease-causing proteins that are
difficult to target with conventional methods. Examples of successful PROTACs
include molecules that interact with the E3 ubiquitin ligases CRBN or VHL on
one side of the chimeric molecule, and selected target proteins like the Andogen
Receptor or BRD4 on the other side of the molecule, leading eventually to the degradation
of the target proteins by the ubiquitin-proteasome pathway.

We have developed ULTImate
YChemH, a powerful chemical biology tool to identify the direct protein targets
of small molecules. It is a unique screening platform based on an improved
Chemical Yeast Three-Hybrid technique which allows unbiased and exhaustive in vivo screening of
the entire proteome from a given tissue or cell line. The absence of any
washing steps contributes to its high sensitivity. In addition, each putative
interaction partner is tested individually, eliminating the competition by abundant
or strong binders.

We are now adapting this
technology to the screening of Protein Degraders in order to identify
potential new targets as well as off-targets of these molecules.