Figure 1: Mechanism of action of degraders based on the autophagy-lysosome system and endosome-lysosome system.
by Fabienne Charrier-Savournin, Life Sciences Technology Platform High Content Reagents Leader, and Volker Eckelt, Director Drug Discovery, Life Sciences Segment, Revvity, Inc.
Abnormal protein expression or activity has been linked to the development of many devastating conditions, including cancer, autoimmune diseases, and neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s. These conditions often involve the misfolding, aggregation, or accumulation of proteins, leading to cellular dysfunction and disease pathology. What if these disease-causing proteins could be selectively eliminated to potentially cure the condition? This is the premise behind targeted protein degradation (TPD), an emerging drug modality that offers the potential to probe biological pathways and target proteins that have previously been considered “undruggable.”
TPD exploits the cellular degradation machinery to selectively target a protein for degradation with the potential for improved therapeutic efficacy compared to traditional small-molecule inhibition and the possibility to discover and validate novel targets. The field of TPD has grown rapidly since it was first described in 20011, with Companies dedicating significant resources to develop TPD-based therapies resulting in over 20 degraders in clinical development2. In addition, there are numerous collaborations between industry and academia focused on advancing the tools and technologies required to develop novel therapeutic degraders.
Endogenous Degradation Systems
The concept behind TPD is to hijack the naturally occurring protein degradation systems within cells using specially designed proteins (“degraders”) that can selectively degrade disease-causing proteins. There are two major endogenous protein degradation systems: the ubiquitin-proteasome system (UPS) and lysosomal degradation pathway (LDP). The UPS is involved in degrading damaged, misfolded, and short-lived proteins, while the LPD is responsible for degrading long-lived proteins and organelles. Both systems are essential for the normal regulation of cellular functions such as cell growth and apoptosis.
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