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Click. Screen. Degrade. A Miniaturized D2B Workflow for Rapid PROTAC Discovery.

Marko Mitrović1,2, Francesco Aleksy Greco1,2,3, Yiliam Cruz García4

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Summary
This summary is machine-generated.

This study introduces a novel workflow for synthesizing and evaluating Proteolysis-Targeting Chimeras (PROTACs). The direct-to-biology approach accelerates the discovery of targeted protein degraders by bypassing purification steps.

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Targeted protein degradation is a rapidly advancing field.
  • Developing Proteolysis-Targeting Chimeras (PROTACs) is challenging due to the lack of rational design methods.
  • Current methods often involve lengthy synthesis and purification processes.

Purpose of the Study:

  • To develop a streamlined workflow for PROTAC synthesis and evaluation.
  • To overcome the limitations of traditional PROTAC development.
  • To enable rapid identification and optimization of PROTAC drug candidates.

Main Methods:

  • A direct-to-biology approach combining high-throughput, semi-automated synthesis with direct cellular assay evaluation.
  • Utilizing copper-catalyzed azide-alkyne cycloaddition for efficient PROTAC synthesis at the nanomole scale.
  • Implementing a workflow that bypasses the compound purification step.

Main Results:

  • Demonstrated general applicability of the workflow across four diverse targets.
  • Achieved PROTAC synthesis in reaction volumes as low as 5 μL.
  • Enabled synthesis and evaluation of hundreds of PROTACs within days.

Conclusions:

  • The developed workflow significantly accelerates PROTAC discovery and development.
  • This approach facilitates comprehensive target degradability assessment and E3 ligase selection.
  • The methodology offers a powerful tool for advancing targeted protein degradation strategies.