Understanding the nuances of targeted protein degradation

Bifunctional degrader molecules (also known as PROTACs) and molecular glues recruit proteins to E3 ubiquitin ligases. The formation of a ternary complex between PROTAC, ligase, and the protein of interest leads to the ubiquitination and subsequent degradation by the proteasome. Researchers are leveraging this cellular process and transforming drug discovery by developing drugs for targets that cannot be inhibited and were considered “undruggable.”

In the first part, Alessio Ciulli, Ph.D. (Professor of Chemical and Structural Biology, School of Life Sciences, University of Dundee) shows how a PROTAC can “glue” the ligase and the target protein together by forming ternary complexes. He then demonstrates that cooperative, stable, and kinetically long-lived ternary complexes drive faster and more profound protein degradation.

In the second part, Stewart Fisher, Ph.D. (Chief Scientific Officer, C4 Therapeutics) discusses how the degraders act as catalytic activators for an E3 ligase to initiate target protein ubiquitination and how he’s applied an enzymology framework to characterize cellular degradation data. He also shows how these insights are used in pharmacodynamic modeling and predictions.

NanoTemper tools are helping researchers characterize interactions involving PROTACs, molecular glues and other TACs.

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