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eBriefing

Understanding Targeted Protein Degradation

Understanding Targeted Protein Degradation
Reported by
Pinelopi Kyriazi

Posted November 18, 2019

Pinelopi Kyriazi is a PhD candidate in neuroscience and a science writer in New York.

Presented By

Biochemical Pharmacology Discussion Group

The New York Academy of Sciences

Overview

Many disease-causing proteins cannot be targeted with traditional pharmacological approaches. As a result, more than 85% of the human proteome is “undruggable.” But in recent years, a novel technology called proteolysis-targeting chimeras (PROTACs) has emerged as a method to target and degrade such disease proteins. PROTACs are bifunctional small molecules that bring together a target protein and an E3-ubiquitin ligase, which leads to degradation of the targeted protein by the proteasome. The advantage is that PROTACs can degrade proteins regardless of their function, making it possible to target mutated or overexpressed proteins. Additionally, they can be designed into effective oral agents, making them therapeutically viable.

Learn more about the latest advances in targeted protein degradation and the benefits of this approach over traditional inhibitors in this summary of our September 24, 2019 symposium.

Symposium Highlights

  • Substrate unfolding is the rate-limiting step in protein degradation.
  • Higher binding affinity, increased cell permeability, and improved residence time make dBET6 a better degrader than dBET1.
  • The research in protein degradation has revealed insights to the mechanistic biology, but more advancements are needed to translate the science into medicine.
Chemical Considerations for Degrader Design
Anatomy of a Chimeric Protein Degrader
Applications of Targeted Protein Degradation