Targeted protein degradation is an innovative new therapeutic approach that works by completely removing disease-associated proteins instead of inhibiting them. This approach can be used to develop more specific therapeutics with higher success rates that can target previously “undruggable” proteins.
Mass spectrometry (MS) based proteomics is the perfect tool for developing targeted protein degraders , providing valuable data on target binding, degradation selectivity, mechanism of action, efficacy, and safety. At Biognosys, our research service platforms – TrueDiscovery , TrueTarget®, and TrueSignature® – can support the discovery and development of TPDs from early discovery, through preclinical studies and eventually to first-in-human trials (Figure 1). In particular, TrueSignature® employs Parallel Reaction Monitoring (PRM) and customizable protein panels, supported by our SpectroDive™ software, for precise TPD analysis.
Until recently, targeted protein degradation had only been clinically proven in oncological diseases. The recent KT-474 trial marks the first clinical trial of a degrader for non-oncology indications, ushering in a new era for the field. In this blog, we will explore the progress in targeted protein degradation research over the years and look at where it might be heading in the future.
Figure 1: Applications of Biognosys’ MS-based proteomics services that support the development and discovery of targeted protein degraders.
In 2019, the first targeted protein degraders, ARV-110 and ARV-471, entered human clinical trials for prostate cancer and breast cancer respectively. ARV-110 and ARV-471 are a type of targeted protein degrader known as PROTACs (proteolysis-targeting chimera) or heterobifunctional degraders. These molecules consist of two ligands connected by a linker, where one ligand binds to a target protein and the other binds to an E3 ubiquitin ligase, which subsequently flags it for destruction by the cell’s own degradation machinery.
As targeted protein degradation is a novel therapeutic approach, several concerns were initially raised about its safety and efficacy. However, the phase I trials of ARV-110 and ARV-471 demonstrated that they are effective against target proteins, safe for human use, and have a therapeutic effect. Since then, both ARV-110 and ARV-471 have progressed to phase II clinical trials, and more than 15 targeted protein degraders have entered clinical trials.
These results have solidified the therapeutic viability of targeted protein degraders and opened the door to new realms of possibility in targeted protein degradation research.
Until very recently, all of the targeted protein degraders in clinical trials aimed to treat various types of cancer. But there’s more to TPDs on the horizon.
In late 2023, the first clinical trial of heterobifunctional degraders to treat non-oncological indications was published in Nature Medicine. In this study, Kymera Therapeutics showcased the safety and tolerability of KT-474 for the treatment of hidradenitis suppurativa (HS) and atopic dermatitis (AD).
KT-474 is a heterobifunctional degrader that selectively targets IL-1 receptor–associated kinase 4 (IRAK4). IRAK4 is a master regulator of the immune system, playing an essential role in triggering signalling pathways implicated in various autoimmune diseases, such as HS and AD. The challenge is that IRAK4 functions as both a kinase (an enzyme) and a scaffold in immune signalling. This means that inhibiting its kinase activity alone, using traditional drugs such as small molecule inhibitors, is insufficient to produce a therapeutic effect.
An unbiased proteomics experiment was first performed to investigate the selectivity of KT-474. Subsequently, a targeted proteomics panel was developed for pharmacodynamics (PD) monitoring on Biognosys’ TrueSignature® platform. In this clinical trial, the PD panel was deployed to analyse isolated peripheral blood mononuclear cells and skin biopsies. Results revealed that KT-474 selectively degraded IRAK4 without affecting other known inflammatory substrates, providing evidence for its use in the treatment of HS and AD.
This trial paves the way for expanding the therapeutic horizons of targeted protein degraders beyond oncological indications. Defective protein degradation has been linked to a variety of disorders, including Parkinson’s disease, muscular dystrophy, Alzheimer’s disease, cardiovascular disease, Huntington’s disease and more. The success of the KT-474 trial could lead to further research into applying similar strategies to tackle various diseases, broadening the scope of targeted protein degradation applications.
This is an exciting time to be involved in targeted protein degradation research, and we look forward to exploring the future of targeted protein degradation alongside our customers. For more information about how our TrueDiscovery®, TrueTarget®, and TrueSignature® platforms can help guide you from early-stage screening to clinical studies, take a look at our previous targeted protein degradation blog. And if you’d like to discuss how we can contribute to your scientific goals, get in touch.