Proteolysis-targeting chimeras (PROTACs) are revolutionizing drug discovery by targeting proteins that were previously considered “undruggable.” These molecules work by bringing the target protein into close proximity with an E3 ligase, triggering natural degradation pathways. Understanding the formation of the ternary complex is key to optimizing PROTAC design for efficient protein degradation.
Robyn Stoller, a business development manager at Cytiva, explains that traditional small-molecule drugs rely on direct binding to an active pocket on the target, limiting potential therapeutic targets. In contrast, PROTACs offer a wider range of targets because they do not require an active pocket. The formation of a ternary complex is essential for degrading the target, and studying this process is crucial for improving degradation efficiency.
Surface plasmon resonance (SPR) technology is playing a critical role in characterizing PROTACs. This real-time binding signal allows for accurate measurement of kinetic rate constants without the need for fluorescent labels on molecules. SPR has been effectively used to study ternary complex formation and stability, leading to insights that correlate improved kinetic rate constants with rapid target degradation.
Recent studies have shown the potential of SPR technology in optimizing PROTAC design and evaluating the affinity of candidate molecules. The advancement of SPR technology, such as the Biacore 1 Series with advanced injection features, is expected to further enhance its application in PROTAC research and development. Researchers can now study complex formation mechanisms in more detail, aiding in the development of targeted protein degradation therapies.
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