Targeted protein degradation is an exciting new drug discovery strategy that promises to reach previously undruggable proteins, expanding the clinically useful range of the proteome. Here, we explain how this new therapeutic approach works and how proteomics can support its transition to the clinic.
Drug discovery is a notoriously difficult process, with an estimated 90% of drugs failing before they reach the clinic (Sun et al., 2022). There are many reasons for this, including low compound specificity, inadequate pre-clinical models, or underperforming biomarkers.
A further problem for the industry is that many drugs work in a similar way, often by using small molecules to inhibit the function of enzymes or receptors. Although employing this tried-and-true strategy can help to increase the chances of success, its utility is limited to specific groups of drugs with suitable drug binding pockets, leaving vast swathes of the proteome untouched. And because many proteins in the same class have similar structures, there can also be issues with selectivity.
A prime example is the large families of protein kinase inhibitors, which share a similar structure due to conserved substrate binding sites. A drug targeting an active site in one protein may also bind to others, leading to off-target toxicity and the potential discontinuation of drug candidates (Grossman and Adler, 2021).
These two issues of ‘drugging the undruggable’ and developing more specific therapeutics are key challenges for the pharmaceutical industry. Targeted protein degradation (TPD) offers a way to overcome both these challenges by abrogating the function of disease-relevant proteins in another way: removing them altogether.
Targeted protein degradation works by harnessing the way cells naturally get rid of damaged or old proteins. In this process, known as the ubiquitin-proteasome pathway, proteins are tagged for destruction by the ubiquitin protein. In turn, this modification directs it toward the proteasome, the cellular machinery for protein degradation.
Protein degraders are small molecules that are designed to engage this pathway in a highly specific way by bringing a desired target protein together with the E3 ligase, which directs ubiquitination. Once this happens, the target protein is tagged by ubiquitin and sent to be broken down.
Since the initial development of this approach in the early 2000s, it has come a long way. Thanks to their ability to remove disease-related proteins in a matter of minutes and in a reversible manner, protein degrader drugs for various types of cancer and autoimmune disease are already in advanced-stage clinical trials (Mullard, 2021).
Mass spectrometry proteomics is the key to making protein degraders a success (Zhang et al., 2021).
This technology, which can identify and quantify thousands of proteins in cells, tissues, and biofluids, can help to answer vital questions across all stages of the drug development pipeline for these exciting novel therapeutics.
In the early discovery stages of protein degrader development, mass spectrometry proteomics can profile the selectivity of lead compounds. It can also reveal vital information about mechanism of action (including ternary complex formation and E3 ligase recruitment), tissue and cell line selectivity, target availability, and rate of protein target turnover.
In the pre-clinical stages, mass spectrometry offers the advantages of being applicable across species and sample types and enabling multiplexed quantification. For example, our TrueDiscovery™ platform can characterize the degradation profile of new protein degrader therapeutics and monitor protein turnover rates to help developers prioritize promising leads.
Targeted proteomics approaches, such as our custom TrueSignature™ panels can aid understanding of pharmacodynamics by measuring the degradation levels of the target protein achieved by different doses of the drug. This all contributes to better understanding the efficacy and safety of drug candidates, which is critical to preventing costly problems further down the line.
The precise and multiplexed quantification of pharmacodynamic markers offered by mass spectrometry is also critical at the clinical trial stage to drive the development of more informed biomarkers for patient response.
At Biognosys, we strive to be at the cutting edge of proteomics and are continually driving forward new applications in drug discovery and development.
We consider targeted protein degradation one of our key therapeutic areas and are working with collaborators at the cutting edge of the field, supporting them to develop and characterize the next generation of game changing therapeutics. Find out more about our progress in this area in our next blog.
Get in touch with our expert advisors to discuss how we can accelerate your targeted protein degrader drug development today.