Protein targeting chimeras (PROTACs) are double headed molecules that bind to E3 ligase at one end and the protein of interest (POI) at the other. Our team can synthesize compounds and develop assays for PROTAC drug discovery projects by drawing on their PROTAC project experience.

PROTACs in Drug Discovery

PROTACs are bi-valent ligands containing a binding moiety or “warhead” that binds to the target protein and, through a chemical linker, is connected to a “warhead” that binds to an E3 ligase such as Cereblon (CRBN) or Von Hyple Ligase (VHL).

Other E3 ligases also exist but mostly CRBN or VHL have been used to date. The target protein warhead binds to the target while the E3 ligase warhead binds to the CRBN or VHL. 

By bringing the proteins into close proximity, the ligase ubiquitinates lysine then groups on the target protein identifying the protein for degradation. Multiple ubiquitin forming chains are required for target degradation.

Targeted protein degradation

PROTAC Assay Development

Charnwood Discovery successfully employs screening strategies and methodologies for accurately measuring protein degradation.

When considering the development of an assay for PROTACs, we take into account the significant degree of chemistry required for the synthesis of PROTAC molecules. Consequently, this makes it unlikely that clients will have many thousands of molecules to test. This forethought and planning often results in time and cost efficiencies. 

As a result of this lower though-put, a JESS-based immunoblotting (western blot) assay represents an appropriate approach that can be used with recombinant cells, primary cells, and tissues from PK/PD in-vivo studies. 

Additionally, at Charnwood Discovery we have invested in the bio-techne Jess technology, thus eliminating many of the error-prone steps alternative approaches require.

TPD