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Intrinsic signaling pathways modulate targeted protein degradation

Yuki Mori1,2, Yoshino Akizuki1,2, Rikuto Honda1,2

  • 1Laboratory of Protein Degradation, Institute for Advanced Life Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.

Nature Communications
|July 2, 2024
PubMed

Insights

Targeted protein degradation can be enhanced by inhibiting cellular signaling pathways. Inhibitors of PARG, PERK, and HSP90 boost the degradation of cancer targets like BRD4, sensitizing cells to apoptosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation is a promising drug discovery approach.
  • Regulatory mechanisms controlling targeted protein degradation are not fully understood.

Purpose of the Study:

  • To identify cellular signaling pathways that modulate targeted protein degradation of BRD4 and related neosubstrates.
  • To investigate the mechanisms by which signaling pathway inhibitors enhance PROTAC-mediated degradation.

Main Methods:

  • Utilized Proteolysis-Targeting Chimeras (PROTACs) based on CRL2-VHL and CRL4-CRBN.
  • Investigated the effects of inhibitors targeting poly-ADP ribosylation (PARG), unfolded protein response (PERK), and heat shock protein 90 (HSP90).
  • Analyzed ubiquitylation patterns and ternary complex formation.

Main Results:

  • PARG inhibition (PDD00017273) promotes BRD4 degradation by facilitating chromatin dissociation and enhancing ternary complex formation.
  • HSP90 inhibition (luminespib) enhances BRD4 degradation post-ubiquitylation.
  • PERK inhibition (GSK2606414) also enhances degradation.
  • These signal inhibitors sensitized cells to PROTAC-induced apoptosis.

Conclusions:

  • Cell-intrinsic signaling pathways can counteract chemically induced target degradation at multiple steps.
  • Inhibitors of specific signaling pathways can overcome these counteracting mechanisms, enhancing targeted protein degradation.
  • This study reveals a druggable strategy to potentiate PROTAC efficacy in cancer therapy.

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