Targeted Protein Degradation (TPD) drug discovery has opened the door for developing compounds that interact with and remove proteins from the normal, and abnormal, milieu of the cell. This is with the intention of removing the effect these proteins have on normal cellular function and disease aetiology.
Charnwood Discovery has several established techniques to help our clients build and develop a robust drug discovery pipeline for PROTACs and molecular glues.
Our Track Record
TPD is a highly appealing approach in drug discovery for several reasons:
- Degraders can partially or totally remove the target protein from the cell, thereby removing the deleterious effect of the protein in the disease aetiology
- Degraders are exquisitely selective and can be used as target validation tools (in place of siRNA) to examine the physiological effects of the protein
- Degraders have the potential to drug the “undruggable” genome by depleting / removing proteins that do not have a traditional enzymatic binding pocket that is typically used for drug discovery
For over 20 years, the drug discovery fraternity has tried and failed to target protein–protein interactions with small molecules. Targeted Protein Degradation drug discovery represents an opportunity to partially or completely remove one of the interacting protein pairs to ablate or remove the elicited response.
How Does Targeted Protein Degradation Work?
There are a number of pathways that we can take advantage of when designing TDP molecules. These include the proteasomal (PROTACs and Molecular Glues), the lysosomal (LYTACs) and autophagy (AUTACs)
By harnessing the natural degradation pathway of the ubiquitin-proteasome system (UPS), PROTACs and molecular glues stabilize the interaction between an E3 ubiquitin ligase and the target, allowing destruction by the proteasome.
This enables the targeting of proteins that traditionally have been more difficult to target with small molecules. Those with broad shallow pockets are a prime example. PRTOACs and molecular glues target the interaction between E3 ligase and the protein of interest (POI) but work via different mechanisms.
Figure 1: diagram of PROTAC and molecular glue. a) A PROTAC molecule interacting with the protein of interest (POI) and E3 ligase bring them into close proximity. b) Molecular glue induces the interaction between a POI and E3 ligase.
PROTACs are double headed “bi-valent” molecules with two binding “warheads”, one that binds the POI, whilst the other binds the ligase, both are joined by a linker.
Molecular glue are smaller mono-valent molecules that appear to stablise the interaction between the ligase and the POI. In both cases this interaction forces the POI into close proximity with the ligase, allowing the ligase to add ubiquitin to lysine groups on the POI. Chains of ubiquitin on lysine groups target the protein for destruction.
Screening Assays for TPD
Fundamentally, a TPD assay must detect changes in protein concentration. The approach chosen is dictated by several factors including sensitivity, simplicity, reproducibility, cost of goods and throughput.
Click on the sections below for more detailed information on the available development assays for PROTAC and molecular glues, or select ‘Contact Us’ for a discussion on your requirements.