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Structure-Based Design of a Macrocyclic PROTAC.

Andrea Testa1, Scott J Hughes1, Xavier Lucas1,2

  • 1Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK.

Angewandte Chemie (International Ed. in English)
|November 21, 2019
PubMed
Summary
This summary is machine-generated.

Macrocyclization enhances proteolysis-targeting chimera (PROTAC) design by constraining molecules. This strategy improved selectivity for BET protein bromodomains, demonstrating potential for more potent and specific targeted protein degradation.

Keywords:
drug designmacrocyclesprotein structuresprotein-protein interactionsproteolysis-targeting chimeras (PROTACs)

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Structural Biology

Background:

  • Macrocyclization is a strategy to stabilize bioactive conformations of molecules.
  • This approach has been used for enzyme inhibitors and receptor antagonists but not previously for bifunctional molecules like proteolysis-targeting chimeras (PROTACs).
  • PROTACs are designed to bring proteins together for targeted degradation.

Purpose of the Study:

  • To design and synthesize a macrocyclic PROTAC by incorporating a cyclizing linker into the BET degrader MZ1.
  • To validate the rational design of the macrocyclic PROTAC through structural and biophysical studies.
  • To evaluate the impact of macrocyclization on PROTAC potency and selectivity for BET proteins.

Main Methods:

  • Design and synthesis of a macrocyclic PROTAC (macroPROTAC-1) based on the BET degrader MZ1.
  • Co-crystallization of macroPROTAC-1 in a ternary complex with VHL and the second bromodomain of Brd4.
  • Biophysical assays to assess binding affinity and selectivity for BET bromodomains.

Main Results:

  • A co-crystal structure confirmed the successful ternary complex formation and validated the rational design.
  • Macrocyclization resulted in enhanced discrimination between the second bromodomain of Brd4 and the first bromodomain.
  • Despite a 12-fold decrease in binary binding affinity for Brd4, macroPROTAC-1 showed comparable cellular degradation activity to MZ1.

Conclusions:

  • Macrocyclization is a viable and advantageous strategy for designing PROTACs.
  • This approach can enhance the potency and selectivity of PROTACs, particularly for distinguishing between homologous targets like BET bromodomains.
  • The study provides a foundation for developing more effective and specific targeted protein degradation therapies.