Protein Degrader Building Blocks
Targeted protein degradation (TPD) is a novel approach in drug discovery to effectively infiltrate cell’s proteasomal degradation pathway and quickly eliminate target proteins from cells. This strategy has the potential to develop new therapeutics that differ considerably from classical inhibitors and is even viable for accessing “undruggable” protein targets and difficult-to-treat diseases.
Our diverse portfolio of protein degrader building blocks allows you to easily generate libraries of protein degraders that can be screened for effective degradation of your target proteins from cells. Our protein degraders, such as proteolysis targeting chimeras (PROTAC® molecules), are bifunctional molecules with three primary components: a ligand at one end that targets the protein of interest (POI); a second ligand at the opposite end that binds an E3 ligase; and a crosslinker in the middle that joins the two ends. The simultaneous degrader binding of two proteins brings the POI in close enough proximity for polyubiquitination by the E2 enzyme associated to the E3 ligase, which flags the POI for degradation through the proteasome.
Related Technical Articles
Partial PROTACs are a collection of crosslinker-E3 ligand conjugates with a pendant functional group for covalent linkage to a target ligand.
Targeted protein degradation (TPD) is an emerging drug discovery strategy that allows access to difficult-to-treat diseases.
The precise design of small-molecule target degraders is crucial for successful protein degradation. Even slight alterations in ligands and crosslinkers can affect binding to the POI or E3 ligase. Thus, many analogs are synthesized, varying each structure slightly, and screened in cells to determine the optimal degrader for target degradation. Our degrader building blocks are a collection of crosslinker-E3 ligand conjugates with a pendant functional group for covalent linkage to a target ligand to streamline synthesis. Since the same functional group is present across a series, one target ligand can be conjugated to several degrader building blocks simultaneously for facile library generation and subsequent screening.
Our protein degrader building blocks are permutations of the following components:
- Ligands targeting the E3 ligase Cereblon (CRBN) or von Hippel–Lindau (VHL)
- Crosslinkers with varied lengths and compositions
- Conjugation sites with reactivity for common functional groups
Advantages of our Protein Degrader Building Blocks
- Compatibility: Linkers conjugate to common functional groups present on target ligands.
- Molecule design: The strategic variety of the combinations of linkers and ligands aids the design of target degraders.
- Synthetic time-saver: The E3 ligand-crosslinker conjugates decrease the amount of time spent on degrader synthesis.
- Library generation: Using degrader building blocks with the same conjugation site enables the simultaneous generation of several degraders via parallel synthesis.
PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
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