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Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.

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Macrocyclization enables novel Proteolysis Targeting Chimeras (PROTACs) like SHD913, overcoming the hook effect for potent Brd4 degradation and improved metabolic stability in cancer cells.

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Macrocyclization enhances drug properties but is challenging for Proteolysis Targeting Chimeras (PROTACs).
  • PROTACs face challenges like the 'hook effect', limiting their efficacy.
  • Brd4 protein is a key target in cancer therapy.

Purpose of the Study:

  • To design and synthesize the first series of "Head-to-Tail" macrocyclic PROTACs.
  • To evaluate the efficacy, specificity, and stability of novel macrocyclic PROTACs targeting Brd4.
  • To elucidate the mechanism of action and structural basis for macrocyclic PROTAC-mediated protein degradation.

Main Methods:

  • Rational design and synthesis of macrocyclic PROTACs.
  • In vitro protein degradation assays (DC50) and cellular assays (NanoBRET).
  • Biophysical assays, co-crystal structure determination, and molecular dynamics simulations.

Main Results:

  • The macrocyclic PROTAC SHD913 demonstrated potent Brd4 degradation with low nM DC50 values.
  • SHD913 largely overcame the 'hook effect' and showed improved metabolic stability.
  • SHD913 exhibited positive cooperativity, induced de novo protein-protein interactions, and outperformed existing macrocyclic PROTACs.

Conclusions:

  • Macrocyclization is a feasible strategy for designing effective PROTACs.
  • Macrocyclic PROTACs like SHD913 offer advantages in potency, specificity, and stability.
  • The study provides structural insights into macrocyclic PROTAC-mediated ternary complex formation and protein degradation.